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The Chiron Program User's Manual

1. EN 114 Move Delete secos aot fons bat 114 Sealen Hm 115 eme Nsectetur n sema tessile oM EL Lora MADE acca 115 pr 116 Real Time Module erro Ia erri Re ere Ia per as d cre E PAEEU 116 12 1 Hardware config ration soi ete ieee Sa vasa ree Re n eo ed ay E Ee pee ios est ee scele te ab vex Prae cedere 117 12 2 Working example Tor Real Time deed eto oe e t gas hee doe a E Dee oe SE Ete o OUT 117 12 3 Real Time Commands eee eret esie rece p eq e e e alergia e 118 Current ioo ette mei etos ie ee eerte ee 118 118 INKS eod oso eden haod ivt 118 Moye E 119 119 Translates E 119 Si brc M 120 Rotate seis 120 AUO RO eats 121
2. 71 HUE 71 PEE 71 EPIS ERE EE 72 HE 72 SHOW Segment mE 72 hine EE 73 CLAP ciem ED RO HN FEE EP ORE SEE SEP CE e CEPR ER RE EEEPR MEER REPRE 73 demens eS 73 74 CAPS cocos e vind edad e exse ese eee ense e d a 74 8 1 CAPS OVELVIEW ess sess RE 75 8 2 Worlang examples for OSEERE 80 8 3 Cleaved and reshaped precursors 81 8 4 Working examples for cleaved and reshaped 8 83 8 5 The More Optom ier erect etos emu sees beds Pet ge clases 83 8 6 The Match command emi ertt estes P reborn ERR 84 8 7 Matching a given 86 8 8 Working examples for Match t e Ete t te sates EE E E ET ea eaves 87 8 9 Aromatic DFeCUrsOES o o o LR ERR Ue E A tdi e SATs ee RA 88
3. aes pene 27 Real Time od ec ee UE e EE Hee 27 Ba eee ba Q 27 Molecular Compositions eo RERO sos EDEN Rep et td ss Dede urea Tek Ero Eve ERO Oe POPE EUR T eye NS 27 Show 27 show Connectivity Table Sero beo reu E EP EH to Pe ENESE Ere eR er RU 28 Atom Menus sits I 28 Os NS racer ettet Pacte tse seabeateuts Ce a satan se tues 28 uc CEDE 29 Periodic Table leere RE e RE Een ERR dees E CERREREEPRR 30 Options Menu tI EIDEM giicp ee Ip E 31 Drawing Options 8552 IR eve eq Sa Sets peteret Ter E EE ted 31 Drawing Options 8 3 2 reser hoe So eint ugs 31 Progr m Preferences odio d t pr Ha Re ER ebore REP EIN PR 32 Color Preferences MI
4. 34 aM EP 36 36 Ori Context 36 4 m P 37 CARS IA Rm 37 4 1 Acychc and alicyclic molecules 2 2 tette Ee re SIR reb easet Eee et Reb eo eas et pP ea Pos 37 4 2 Carbocyclic molecules IERI peer s ups 37 4 3 Stereochemical depiction of bonds 0 iia de terree Ere Preig I HE RP REPE PY ERR ERE SERERE e dE 39 4 4 Rules and comments on functional hes ren 40 4 5 Working example drawing molecules ss sisi 12 ite ett eite UR y Eee Re Re T eR RR RR 43 4 6 Adding to the precursor database oerte tenen eere ree dese tuere ous s etus Pe ee rose Ue Sedet Sg odovere 45 PART dich DUO ne Dele eleanor 46 CARS 2D 8 66 6 6 6 nnn 46 oil 46 ATTOWS xis oeste US e eoe b Dee te SEA EA E etre b E Nee ie 48 PII 49 hi fee EE EI 50 ncc 51 Build e eU e RI o
5. O ETT 89 CAPS 666 hh 89 BUCY uae scons ON 90 Functions ooo eot EN este du cotes ed NT EM M DEDE pin ative 91 Parameters MEI 92 lun OM E EI I EE ERN 95 RSP Rapid Scanning of PLECUESOLS RT B U BMe T 96 RSBC Rapid Scanning of Best 96 EET 97 EE 98 EIE 102 o ev S RE e UN AUN eed set e UM ide dus 103 SAVE JOD decet Sam oie E dene dont Sam tiere dete dU Sex daro e tio ea ed eed eode 103 I oad Job cioe ON EROR E e ee ERI eu cu 103 Delete T n EE 103 MOVE eoe esto US esset d E EDS E ee o e bd E e RV 104 SCrapezssecste c tetto iet cnet uet leue ree 104 lad EET 104 PART 10 105 5 31 0 T PRU TONE sie 105 10 1 Entermg CARS 3Dx Soden ep basta sold vier ects slag pesos is Cuenta ERR SERRE 106 10 2 Molecule representation 2 Doer e pet HE EI e ee e PP ea Ere
6. ROt EET 121 EWS e ed ee a a er neta Renee 121 MAPS A UU DUE E A EN E ining E A 122 SE SSAA E EEE E EE EE EEE AEE 124 e EE 124 log e E E 124 QE 125 APPEND D A cp ES 126 Chiron Interchange 599 tr re ee REI aisles 5 aig sib HO eS e cu E VER x ye pedet 126 APPENDIX 128 Keon Definition Formats cha letus 128 FERREA 131 ACKNOWLEDGMENT Sa 135 Foreword The Chiron Program is the name given to an interactive computer program developed in the laboratories of Professor Stephen Hanessian at the Universit de Montr al The program offers the user some unique capabilities for the analysis and perception of stereochemical features in organic molecules Its strongest attribute is the speed with which it can carry out such operations since these would normally re
7. Gates Tschudi JACS 74 1109 1952 DB CHIRON F MATCH Match 4 P M 1 13 14 1 Figure 8 18 8 8 Working examples for Match The following precursors are in precursor file Match 1 Leukotriene precursor framework carbon atoms are essential 2 Apomorphine phenenylamine portion essential only 3 Fentanyl phenethylamine portion essential only 4 Morphine Hetero atoms and ethylene bridge are non essential 5 Nicotine framework carbons and pyrrolidine N are essential 6 Mescaline all framework carbon atoms and N are essential 7 Octoclothepin phenenylamine portion essential only 8 Psilocin all framework carbon atoms and N are essential 9 Erythronolide A Seco Acid only framework carbon atoms are essential 10 Pseudomonic Acid only framework carbon atoms are essential 11 Compactin framework carbon atoms are essential 12 Erythronolide A only framework carbon atoms are essential 13 Muscarone framework carbons and side chain amino group are essential Forskolin e Load Forskolin and enter the CAPS module On the File dialog select the MATCH file in the CHIRON database then select the Single Precursor item from the CAPS search option menu then enter 9 Erythronolide A Seco Acid in the Precursor text box e Find Use RSP and notice the matching chain on the target You can start another search with Pseudomonic acid Keep the same parameters e Find then ask for number 10 Use
8. e A character indicating if the segment is at the end of a path to be stroked right away S indicates that the path is to be drawn and that the pen shade is specified immediately afterwards s indicates that the path is to be stroked in a shade determined at runtime X indicates that the path is not to be stroked right now 1 128 e Ifthe path is to stroked there must be an additional character defining the appropriate line width for the path L indicates that the line width is fixed in the file and determined immediately afterwards indicates that the line width will be set at runtime Blanks one or more must separate each of theses items The coordinates of the segment s extremities and of the center of curve if the segment is an arc must be defined relative to the control points The first control point is set at coordinates 0 0 and the second one is at 1 0 for V and H icons and at 1 1 for R icons When you define an icon place the points where they would be if the real coordinates of the control points were always 0 0 and 1 0 or 1 1 Example defining the left accolade The vertical left accolade is a V icon and we will separate it into six segments We start drawing the accolade at 0 0 its first control point will therefore represent the beginning of the icon The first segment is an arc leading to 1 6 1 6 As we need a quarter of a circle to represent it correctly the center of the correspond
9. The Chiron Program USER S MANUAL Version 5 0 Chiron Program PRECURSOR MANUAL Version 5 0 An interactive computer program for the analy sis and perception of functional and stereochemi cal features in molecules and for the selection of precursors in organic synthesis Featuring CARS 2D Computer Assisted Reaction Schemes CASA Computer Assisted Stereochemical Analysis CAPS Computer Assisted Precursor Selection CARS 3D 3 Dimensional Drawing and Simulation REAL TIM E Real time 3D molecule manipulation The Chiron Team Benoit Larouche Analyst Benoit Carrier Programmer Xinxia Cai Precursor Database Bo Huang Precursor Database Professor S Hanessian Department of Chemistry Universit de Montr al P O Box 6128 Station Centre ville Montr al Qu bec H3C 3J7 FAX 514 343 5728 E mail hanessia ere umontreal ca Copyright 01998 Licensing Information The Chiron program is Copyright 1998 by Professor Stephen Hanessian Universit de Montr al with all rights reserved Both the material and the right to use them are owned exclusively by Prof S Hanessian and Universit de Montr al Please do not duplicate the Chiron program except for your personnal backups You may use the Chiron program on any computer owned by you Trademarks The Chiron Program is a registered trademark of Professor Stephen Hanessian Universit de Montr al Adobe PageMaker PDF and PostScrip
10. 21 90 file formats 23 File List 20 File Menu 15 File organization 15 Fill 49 Find 95 Fischer 69 Flip 59 Floor 31 107 font 25 font size 32 Foreword 5 Formula 22 Function 21 91 functional groups 40 Functions 27 41 G graphic user interface 9 Grid 34 44 53 28 124 Hydrogen 31 32 43 IBM PC 12 Icon 49 Icon Definition Format 128 icon def 128 Identical 71 Identical 72 Import 23 Input precision 32 install sh 10 Installation 10 Invert 115 isotopes 29 J Justification 47 Labels 123 L Amino Acids 51 Large 50 Large Cleave 50 line width 32 Load 18 Load Job 103 Load Number 18 Lone Pair 113 lone pairs 29 M Macintosh 12 MacroModel 23 mainpassword dat 11 Match 84 Matching 93 MDL 23 Menu Bar 15 Meso 71 Mirror 73 Module Menu 26 modules 6 mol 23 mol2 23 Molecular Composition 27 Molecule 34 MOLfile 23 118 83 Move 56 104 Move Axis 119 N 28 Name 22 New Database 20 New File 20 Newman 115 Next 112 No Number 31 normal 29 Notation 9 Number See Atom Number Number Atom distance 32 numbers color 94 Q0 O 28 On Context 36 On Version 36 Options Menu 31 Other 29 P Parameters 92 password 11 26 PDB 23 Peptide 51 Periodic Table 30 Perspective 32 107 Place 97 Points 102 P
11. HO 22 Me 26 Me 24 Me HO 29 Me The C3 C7 and C9 C13 segments are identical superimposable Priority Tree 15 Weight Decreasing Figure 7 1 EN mm P m rem Te 7 65 RS Absolute stereochemical notation assignments for asymmetric centers only excluding compounds with chiral axes planes etc will be executed immediately upon indicating RS The R S designations will appear next to the corresponding centers The algorithm to find the assignment of each stereochemical center uses t he original publication of Cahn Ingold and Prelog see Angew Chem Internat Edit Vol 5 1966 No 4 and Angew Chem Int Engl 21 1982 567 583 There are still some cases that have not yet been implemented see rule 4 below Figure 7 2 rule 0 Nearer end of axis or side of plane precedes further Since we do not consider either plane or axis of symmetry this rule was not implemented rule 1 Higher atomic number precedes lower Fully implemented rule 2 Higher atomic mass number precedes lower Fully implemented OH C 13 Figure 7 3 7 66 rule 3 Seqcis precedes Seqtrans The double bond case E Seqtrans and Z Seqcis is fully implemented even the special case when the E Z configuration can only be computed by using the center we want to determine For cis trans in ring compounds these rules should only be used as a preliminary indicati
12. Indicate this option and point consecutively to the atoms that will be renumbered from the number User Main in the From text box Note that you can have several atoms with the same number 3 From to indicate the number from which to start renumbering Template Reset to reset the start renumbering to 1 1 Reorder Table once you have renumbered a molecule or precursor selecting this romatie command will change the ordering the connection table so that the order in the table POolyaromatic will correspond to the numbers on the screen You don t have to renumber all the atoms just renumber the essential atoms and the program will renumber the rest for you Done Original Numbering if you wish to return to the original numbering for the molecule before you entered the Build dialog and until you selected Reorder Table Template to use predrawn forms to draw molecule There are different sets of templates in CARS 2D and in CARS 3D In CARS 2D the default template set will allow you to draw almost any molecule but if you wish you can build your own template set for a single user or for every user through the main files To use the default set select Template in the Build dialog Now point to any template atom and select a new position for it You can weld templates together to create polycyclic molecules etc If you want to create your own templates just draw them and save them i
13. SAVE EE 19 Replace Molecule 3 55 98 oett etse fee sonet td eie cance n tame donee edt Mane ior estes d mee 19 Replace Molecule Nut bet cede he Pets oe vea ede Yves e gae er en Guede eye sun grues Ee p eine E 19 20 New Databases e eee od cbse dade ooh ad e eh de d evan e e en ae ovate ool cated aa er E deus 20 Remove Database ic sic ce Ld testi editi setis ade iun Mee direiter 20 New ex ueteres eee eH e E p PC ERU E E 20 E 20 Igi Xil 20 ER TE 20 E 22 Scar DiastereGmer 22 Scan Doubler E E E E E 23 Import EX port et ever beet eta ee der 23 edi Wes Hu HEP HERR REE HGB 24 Change Lou 26 ELT 26 ln p 26 e NNDADE P 26 CARS 3D MT 26 26
14. 0 0 000 00 293 687 500 1 3 al 0 0 09 0 0 0 000 00 239 659 500 4 8 2 0 0 10 4 0 0 0 000 00 185 687 500 5 3 0 0 0 0 Aka KA TLIC 5 0 0 0 000 00 132 660 500 6 7 7 4 0 12 1 60 0 0 000 00 81 684 500 5 0 0 0 0 13 N 7 0 0 0 000 00 157 603 500 8 5 5 0 0 1410 8 0 0 0 000 00 216 603 500 7 3 0 0 0 15 0 90 0 0 000 00 400 688 500 1 0 0 0 0 RAK 1610 10 0 0 0 000 00 344 598 500 1 1 0 0 0 AREA AE 17 N 11 0 0 0 000 00 293 747 500 2 0 0 0 0 KAKA 18 1 18 example for Acivicin 2013792 7091 18 1 0 0000000 0 2141 22 6255 6314 3606 63140 3 0 011 Chiron Version A 100 021 Molecule name A100 1 03 Molecule reference A100 1 041 CAS Number Put 0 0 0 for default A100 051 1 if molecule is racemic I1 061 Number of atoms 13 07 15 Description of the molecule One line per atom Atom name A6 X atom number I3 X Value I1 2 X WithNo I1 2 X MatchNo I3 2 X Charge F7 3 X Isotope 2 X Racemic 2 X Position X Y Z 3 I5 X bonds 6 X bond type 6 C 4 181 Number of texts I3 Two lines per text one for the text and one for the description 191 The text A100 1 201 X position 14 X Y position I4 X Font size 14 X text kind I2 3 X text font 2 Text style 7 C 2 X color 1 2 211 Number of arrows One line per arrow 22 X start I4 X Y start I4 X X end 14
15. 2 Amino 3 4 5 trihydroxy pentanoic acid Ref Casiraghi et al T L 35 2423 1994 Database CHIRON File ACYCLIC 5 183 Match P M 1 1 2 2 3 3 4 4 5 5 PRECURSOR 3 SCORE 70 Name L Arabinose Ref Aldrich A9 190 6 Database COMMERCIAL File ACYCLIC 5 10 Match P M 1 1 2 2 3 3 4 4 5 5 PRECURSOR 4 SCORE 70 Name 3R 4R 3 5 Dihydroxy 4 amino pentanoic acid Ref P Garner T L 25 5855 1984 Database CHIRON File ACYCLIC 5 7 Match P M 1 5 2 4 3 3 4 2 5 1 PRECURSOR 5 SCORE 70 Name D Xylose Ref Aldrich X107 5 Database COMMERCIAL File ACYCLIC 5 14 Match P M 1 1 2 2 3 3 4 4 5 5 PRECURSOR 6 SCORE 69 Name 3R 4S Xylulose Ref Aldrich 28 417 3 Database COMMERCIAL File ACYCLIC 5 50 Match P M 1 5 2 4 3 3 4 2 5 1 PRECURSOR 7 SCORE 68 Name L Arabitol Ref Fluka 10870 Database COMMERCIAL File ACYCLIC 5 351 Match P M 1 1 2 2 3 3 4 4 5 5 see how each precursor got its score A table of the precursor match on the target including the points in percentages given for the chemical transformations and the ratio of importance for each center of the target is shown You can also see losses and bonuses 2 4 Dideoxy 2 4 di C methyl D glucose S Hanessian et al CJC 55 1111 1977 DB CHIRON F ACYCLIC 6 78 37 P M 1 1 6 6 ERYTHRONOLIDE A Figure 9 4 PRECURSOR SCORING DETAILS Nam 2 4 Dideox
16. 3 23 If you Import a molecule you will lose the previous molecule on the screen Chiron program lt gt Chemdraw interface The program supports the Chemdraw Connection Table file format Chiron program lt gt Sybyl interface The program supports two formats of Sybyl MOL and MOL2 Make sure you are in the CARS 3D mode do not add hydrogens before going from Sybyl to The Chiron Program Unrecognized atoms will be transferred as carbons Change them using the Atom command For polyaromatic compounds it may be necessary to delete an extra double bond using Draw or Delete Chiron program lt gt PDB interface Note that molecules containing more than 255 atoms are not read and that the only words that The Chiron Program recognizes are ATOM HETATM TER and CONECT Chiron program X Ray interface The X Ray format recognized by the program is the following one line per atom consisting of a chemical symbol A6 and X Y Z coordinates spaced by one space The program reads X Ray data for any cell parameters i e D y lal Ibl Icl Print To print the molecules currently on the screen according to the current options Print From Select Screen to print the information currently on the screen Every molecule in this manual was created using this option To File then inserted into a word processor Select File to print every molecule or precursor in the current file in a format identical to the one found in th
17. Dotted line distance distance between dots in a dotted line 14 Standard arrow head length arrow head length for standard arrows 15 Standard arrow head width arrow head half width for standard arrows 16 Full arrow head length arrow head length for full arrows 3 32 17 Full arrow head width arrow head half width for full arrows 18 Double arrow head length arrow head length for double arrows 19 Double arrow head half width arrow head half width for double arrows 20 Double arrow body width arrow body width for double arrows 2 Equilibrium arrow head length arrow head length for equilibrium arrows 22 Equilibrium arrow head half width arrow head half width for equilibrium arrows 23 Equilibrium arrow body width arrow body width for equilibrium arrows 24 Reversed leave at 0 User Level Level of messages to user Beginner Expert Recover to recover your work Figure 3 7 3 33 Color Preferences This dialog allows you to change the default color settings for some features of the program The 32 virtual colors are saved when you exit the program You can change 32 virtual colors by editing the CHIRON HOME main term def file You can use color indices on a non color terminal and save a molecule with appropriate colors you can then load this molecule on a color terminal with correct color indices or print on a color printer even if the terminal doesn t support any color In all cases
18. Like the file list you can select the current database by selecting the radio button to the left of the database name and turn ON or OFF some databases by selecting the toggle box to the left of the database name Ownership File Kind Figure 3 1 The following figure is a diagram of the file organization including the files that are already on the CD ROM 3 16 ACYCLIC 3 ACYCLIC 4 ACYCLIC 5 ACYCLIC 6 ACYCLIC 7 PLUS AROMATIC AROMATIC CONDENSED CARBOCYCLIC CARBOCYCLIC BRANCHED CARBOCYCLIC BRIDGED COMBINATION HETEROAROMATIC HETEROAROMATIC COND HETEROCYCLIC MACROCYCLIC NUCLEOSIDE POLYAROMATIC POLYCARBOCYCLIC POLYHETEROAROMATIC POLYHETEROCYCLIC STEROID MATCH File organization Molecule Precurso TARGET EXAMPLE EXAMPLE 3D ACYCLIC 3 TEMPLATE ACYCLIC 4 TEMPLATE 3D ACYCLIC 5 L_AMINOACID ACYCLIC 6 D AMINOACID ACYCLIC 7 PLUS e AROMATIC AROMATIC CONDENSED CARBOCYCLIC CARBOCYCLIC BRANCHED CARBOCYCLIC BRIDGED COMBINATION HETEROAROMATIC HETEROAROMATIC COND HETEROCYCLIC MACROCYCLIC NUCLEOSIDE POLY AROMATIC POLYCARBOCYCLIC POLYHETEROAROMATIC POLYHETEROCYCLIC STEROID 10 Leukotriene precursor etc Acivicin 11 Ionomycin Thienamycin 12 Morphine Avermectin Aglycone 13 Butaclamol Forskolin 14 Penem Erythronolide A 15 Macbecin Amphotericin aglycone 16 Nicotine Dihydromevinolin 17 Monensin A Compactin 18 HuperzineA Gibberellic acid 19 Picotox
19. NHX P PE COOX CONX COX CX NHX OX x CXX NHX OX CH3 5 CN SX Ph Figure 4 7 4 4 Chain functions NoF Me CH3 N Aromatic functions H H CX CX SX SX NHX SH A NHX SX X SL pu E Ket BranchC X BranchO Figure 4 8 CLEA CH3 Halo OH NHX Z d x COOX CHO Figure 4 9 Branch functions Me pu As A Ox CH3 Met CX Figure 4 10 Valencies The valencies of common atoms such as C O N S P etc are automatically adjusted and validated by the program For example a primary amine will lose its hydrogens progressively as new bonds are added up to a valence state of 5 After that it will be impossible to add other bonds By default the program will complete the valence number with hydrogens and will assume that H s are connected to the atom The number of H s will appear next to the symbol name in subscript OH Atom Valence Example min max 4 4 Tetravalent sp3 sp2 sp carbon O 2 3 ether oxonium etc N 3 5 amine ammonium nitro etc S 2 6 sulfide sulfonium sulfone sulfoxide sulfate etc 3 6 phosphine phosphonium phosphate etc 4 5 Working example drawing molecules Drawing freehand The following is an attempt to quickly introduce you to drawing a molecule Consult the CARS 2D commands descriptions for details Part 5 The firs
20. SGI you have and its operating system and how and when the program crashed what you were asking of it etc If you get to the Chiron menu and start the program but it does not work properly try the following Verify that the files on the main account are accessible to every user e Verify that the owner of the account is the owner of the files e Verify that all files are in the correct location and that the directory structure is OK If it still refuses to work contact The Chiron Program development team If you find some imperfection in the program or if you have any suggestions please contact The Chiron Program Development Team Benoit Larouche Benoit Carrier Stephen Hanessian laboratory FAX 514 343 5728 E mail hanessia ERE UMontreal CA 2 14 Menu Bar File organization There are two kinds of files Molecule and Precursor and two kinds of ownership User and Main These two factors make 4 different kinds of files that all work the same file commands will work on all 4 file types You can select the current file kind with the Molecule and Precursor radio buttons You can select the current file ownership with the User and Main radio buttons These radio buttons are located in most file operation dialogs The 4 file types are each represented by a maximum of 50 files In each file you can save as many molecules as you want a molecule is a complete screen which means that if there is more than one molec
21. a maximum of 255 atoms that are chemically recognizable The alpha beta designation is used to specify asymmetric centers The user must respect some rules on how to draw molecules The following sections explain some aspects of these rules 4 1 Acyclic and alicyclic molecules Draw acyclic molecules in extended zig zag projections and not as Fischer projections Avoid placing three atoms in a line It is understood that the main carbon chain is in the plane of the paper alpha bonds extend below that plane and beta bonds extend above it OH Me SH OH NH OH Recognized Not Recognized Figure 4 1 4 2 Carbocyclic molecules Do not indent carbon atoms in ring forms Angles should always extend outwards Chair forms are not recognized in 2D since molecules are planar the indented center would be considered in the wrong perspective R S reversed Chair forms are for use in the 3D module use chair forms in 2D for drawing schemes only In the figure below the arrows indicate atoms for which stereochemistry is not recognized 4 37 Not recognized Recognized use 3D drawing mode E l l M All equivalent and recognized 9 0 Not recognized 2D may cause problems at junctures dia Figure 4 2 Trani Aromatic compounds aromatic rings are recognized when fully drawn Enter double bonds according to the type of aromatic ring you want Here are some examples of aromatic rings tha
22. build your own database Since the process is based on pattern recognition the program may suggest the same precursor more than once but shown in different perspectives it may be rotated around an axis etc This may show you different synthetic possibilities for each perspective see next page the example with R 5 hydroxy 2 piperidone in the CAPS analysis of a heterocyclic target Furthermore the program may suggest a precursor which may not be suitable as such but it will make you think of a better one Figure 8 3 CX Inv SELAGINE HO 5 JT R 5 Hydroxy 2 piperidone R 5 Hydroxy 2 piperidone Deanne et al JCS Chem Commun 813 1969 C C Deanne et al JCS Chem Commun 813 1969 DB CHIRON FZHETEROCYCLIC DB CHIRON F HETEROCYCLIC 28 44 P M 1 1 6 9 26 44 P M 1 1 6 2 Figure 8 3 Once the program has selected precursors you may find some to be impractical This is to be expected since the program is only decoding the hidden symmetry of the target for you and expressing it in the precursor and vice versa You have to make the final decision with regards to synthetic feasibility Remember also that there might always be an ideal precursor that was not found because the parameters chosen were too restrictive It is possible to display two target molecules on the screen and ask for precursors for both at the same time In this case number the atoms of the target molecu
23. displayed Stereo display two slightly offset right and left views Double display front and top views This view mode is useful when you work along the Z axis since it is difficult to keep a good perception of distance Left Button Switch from one mode to the next one each time you press it Middle Button The middle button has no effect Right Button The right button has no effect Axis Axis lets you show hide or change the width of the axes Left Button The left button will allow you to enlarge or shrink the axes of rotation by moving the mouse up or down respectively Middle Button 12 118 The middle button will allow you to enlarge or shrink the base of the axes of rotation by moving the mouse up or down respectively Right Button The right button has no effect Move Axis Move rotation center This option lets you detach the center of the molecule from the center of rotation When you use this mode Left Button While pressing the left button move the mouse in the direction you want to move the molecule The molecule will move but not the rotation center A line will be displayed that connects the center of rotation to the center of the molecule Middle Button The middle button lets you move the center of the molecule along the Z axis Right Button The right button will allow you to lengthen or shorten the distance between the center of rotation and the center of a molecule Clipping plane co
24. molecule for reaction scheme purposes These bonds do not hold any chemical significance to the program To change the type of a bond simply select the desired dialog box and point to one or more bonds in the molecule Simple to change back to an ordinary bond Large to change to a large bond as in the precursor framework Cleave to change to a dotted line across the bond representing a cleaved bond Large Cleave to change to a dotted line across a large bond showing a cleave Arrow to change to a large arrow bond like the last bond of the chain for Identical in CASA The arrowhead will point towards the atom nearest to the point you indicate ZigZag to draw racemic bonds using wiggly lines Dash to change to a dashed bond 1 Atom to selectively color atoms with the Atom H color If you select an atom twice it will toggle back to the Atom color You can change the default and highlight atom colors in the Color Preferences dialog All Atoms to color all atoms of a molecule with the Atom H color If there is more than one molecule indicate any atom of the molecule you want to color 1 Bond to selectively color bonds with the Molecule H color If you select a bond twice it will toggle back to the Molecule color You can change the default and highlight bond colors in the Color Preferences dialog All Bonds to color all bonds of a molecule with the Molecule H color If there is more than one molecule
25. sample xterm DECnet Host XDMCP Password 1 1 amp Prompt when connecting Edit None Duplicate Command Processor REXEC Command setenv DISPLAY ME amp amp fusr local bin chiron Dutput Never Display Output w Figure 2 2 e Select the Connect button The next time you will want to start The Chiron Program you will be able to do it simply by selecting the Chiron item from the Connections menu Since a Macintosh has only a one button mouse you will have to use a combination of key mouse events to simulate a 3 buttons mouse If you are using the default eXodus setup you can access the Atoms popup menu right mouse button by pressing the lt Command gt 3 keys on the keyboard To see or change the mouse setup of your X Server select the Server Settings item from the Settings menu then select the Mouse Buttons icon Using Exceed on an IBM PC compatible You can use the Client Wizard provided with Exceed to easily start an xterm session or directly start The Chiron Program You can also easily create shortcuts for them The default Exodus X Server settings does not refresh The Chiron Program s window when you move a dialog on the top of The Chiron Program To solve that problem start the Xconfig program select the Performance button then turn off the Batch Requests toggle button Inside The Chiron Program you can also use the Update command or press the p key to refre
26. structure data files with other programs It is thus possible to work on a molecule with the program transfer Export it to a file and call it back in Isis Chemdraw etc The reverse Import process is also possible This operation is done simply by indicating the Export or Import menu item A file selection dialog will appear with an option menu containing every supported molecule file format Select the desired file format then follow the instructions below to go from The Chiron Program to another program Chiron program gt MacroModel Sybyl MDL MOLfile Synlib PDB SMD X RAY CSSR and ChemDraw CT Draw the structure of your molecule and indicate Export in the File menu Select the desired file format in the option menu type in the file name then indicate OK MacroModel Sybyl MDL MOLfile Synlib and PDB Chiron program Select the Import menu item from the File menu a file selection dialog will appear Locate the file name in the right directory and then click OK If the file name is missing replace the extension Ex mol2 in the Filter text box by then indicate the Filter button Note when transferring a structure from The Chiron Program to another program for minimization 2 D structures will have to be reshaped in the other program Remember that 3 D structures in this program are not energy minimized structures If you are transferring a 3D type structure be sure you are in the CARS 3D module before you proceed
27. structure represents an energy close to the minimum 10 110 CARS 3D Commands You will find in this section all CARS 3D commands in their menu order General information and examples can be found in Part 10 Options not described in this chapter work exactly as in CARS 2D Me Me Bafilomycin A1 HO OH Figure 11 1 The structure of Bafilomycin Al was imported from X ray coordinates in the Cambridge Crystallographic Database see the Import command in Part 3 m pre parem prc pee pu proa pre poems Ss oa ag rum 11 111 Text Arrows Icons Bonds As in CARS 2D Note that the positions of texts arrows and icons are relative to the surface of the screen not the 3D box If the point of view is changed arrows icons and texts will not move Works as in CARS 2D with the exception of the Template command whose sets are different In 3D you cannot select a template by one of its bonds only by an atom Use Draw3D for semi automatic input of molecules in three dimensions Once you have activated the command you can start drawing by selecting Start from the dialog Bond Start initiates the drawing process After selecting Start if you indicate an existing atom Draw3D will propose a bond to be appended to it however if the atom has Back already filled all its valencies you will not be able to start from there If you indicate empty point
28. to be found either in the molecule name or in the reference You can use the wild card in the name For example if you search for WOOD for the reference then you will get some Woodward precursors If you search for DEOXY GLU for the name you can get any precursors that have a DEOXY sub chain followed by anything possibly nothing at all and somewhere after by the sub chain GLU such as 2 Deoxy D GLUCOSE Something like 2 Deoxy 3 Amino GLUCONIC ACID would be also found Search to start a database scan using the current parameters program will search only files that are active and start with the current file See File organization at the beginning of this chapter Those parameters are independent and you can build any combination By default if you don t indicate any parameter then it will accept everything and present molecules one after the other Load to retrieve a saved search You can also Load a normal molecule or precursor file like the Target molecule file Save to save the current scan results Scan this option will propose all molecules or precursors found in the current search result Print to optain a PostScript graphic lising of all molecules found in the current search result Also see the Print From File option from the File menu Scan Exact To locate a precursor or molecule that is currently on the screen into a file It will look into all active databases and files for an exact match Scan Diastereome
29. trial and error If you need some assistance select the Help command which will display on line documention identical to this manual However if you wish to have a simple introduction to this module you can follow the working example in the next section Note that this module is only available on Silicon Graphics workstations Figure 12 1 Ionomycin Ca Salt and Avermectin B were imported from X ray structures 12 116 12 1 Hardware configuration Except for this module the program will run very well under the minimum configuration of Silicon Graphics workstation that is with 8 bit planes For certain options of this module you will need more bit planes The following table gives you the bit planes needed to run some Real options e Atoms Bonds in Flat Shading or Gouraud Shading 24 Z Buffer bit planes Shape Menu See Shape Menu 24 Color bit planes Depth See Shade Menu 24 Color bit planes All the other options 12 Color Bit planes Other options will still work with 8 bit planes but you will loose the most significant bit of the index color In other words when you enter to the real time module every color between 16 and 31 will be replaced by the color between 0 and 15 12 2 Working example for Real Time Enter the program and select the CARS 3D item in the Module menu From the File menu select Current File and choose Example 3D in Main Molecule From the File menu select Load then Forskolin Select Rea
30. will find all molecules that have the molecular formula C5H O5 and has the characters string ose in its name 3 20 Buc File to select the databases and files to scan in See the Current File command Function this command will allow you to select which functional groups you want to find in the database For each function you can specify a function that must be present M or must not be present may or may not be present in a molecule or precursor Also see Show Functions in the Extra menu Commercial this toggle box will allow you to search for commercial product available in your own database However it is not useful with precursors provided with the program since all commercial precursors are in the same database When Commercial is checked the program will search for molecules that have a special character string ex commercial in the reference field You can add a new string by editing the file CHIRON_HOME main commercial dat Here is the content of commercial dat file 3 2 ALDRICH FLUKA EASTMAN MERCK INDEX SIGMA SUMITOMO LANCASTER Formula to scan the database for a specified molecular formula like C6OHIOO7N You can use the wild card to match anything For example if you are searching for the name of all precursors that have 7 carbons and 5 oxygens then ask for C7 O5 Name Ref to scan the database for a specified string
31. you are ready to use your personal computer as an X Server You should also have installed The Chiron Program on your SGI computer Please note that the information in the next sections is not intended as an endorsement We only include the information as we had the possibility to use a demo version of these products In the same way the following information is not intended to be a complete procedure on how to use these softwares but just hints on how to quickly configure them and run The Chiron Program Using eXodus on a Macintosh We will discuss two different ways of starting The Chiron Program using eXodus In both cases you must be sure that your screen type is rooted Otherwise you will encounter problems with a few options of the programs like Show Segments and RSBC e Launch eXodus e Select the Server Settings item in the Settings menu On the left section select the Screens icon the first On the right section of the dialog be sure the screen type is set to Rooted e Click OK 1 Using an xterm e Start an xterm session A Sample xterm is provided with eXodus in the Connections menu e Start The Chiron Program with the usual command 2 Using the connection manager e Select Connection Manager from the Connections menu e Modify the setup so it will lool like 2 12 zm Connection Manager REXEC RSH Client Information New SM Sample Session
32. 121 48 51 5 60 055 33 63 16 x H 16 126 5 92 7 x 7 055 3 95 4 63 997 23 50 3x0 47 998 26 87 2 xN 28 013 10 28 2 xN 28 013 15 68 1 xS 32 060 11 77 1xCl 35 452 19 85 Figure 3 6 H N To replace an existing atom with an oxygen nitrogen carbon sulfur hydrogen or any other 5 atom atoms are carbons by default Select 5 or Other and point to the atom to be changed You can also select any atom by using the periodic table Other Periodic Table You can also press the right mouse button to have access to the Atom popup menu 3 28 Other The Other menu item include atoms or functions in a molecule other than those available directly All the atoms of the periodic table are recognized by the program but their names must be entered correctly identifies a Cobalt atom but not CO cO or co An atom function name is limited in length to 100 characters The program can also handle lone pairs To add a lone pair to a molecule type Ip or and indicate the atom you wish to change to a lone pair Two points will appear in the work area to signal the presence of a lone pair It is also possible to insert different isotopes of an atom to add a deuterium atom enter D for a tritium atom type Other isotopes are specified by typing their atomic symbol a star and their atomic weight ex C 13 It is also possible to ins
33. 2 1992 The Psychobiological Basis of Heuristic Synthesis Planning Man Machine and the Chiron Approach Stephen Hanessian Jonathan Franco and Benoit Larouche Pure amp Appl Chem Vol 62 No 10 pp 1887 1910 1990 Computer Assisted Analysis and Perception of Stereochimal Features in Organic Molecules Using the CHIRON Program Stephen Hanessian Jonathan Franco Gilbert Gagnon Dominic Laram e and Benoit Larouche J Chem Inf Comput Sci Vol 30 No 4 pp 413 425 1990 Total Synthesis of Stephen Hanessian Anne Marie Faucher and Serge Leger Tetrahedron Vol 46 No 1 pp 231 243 1990 Synthetic Studies on the Mevinic Acids Using the Chiron Approach Total Synthesis of Dihydromevinolin Stephen Hanessian Patrick J Roy Marino Petrini J Hodges Romano Di Fabio Germano Carganico J Org Chem Vol 55 No 22 pp 5766 5777 1990 Progress in Natural Product Chemistry by the Chiron and Related Approaches Synthesis of Avermectin Stephen Hanessian Antonio Ugolini Paul J Hodges Pierre Beaulieu Daniel Dub and Christiane Andr Pure amp Appl Chem Vol 59 No 3 pp 299 316 1987 1 2 Overview of the modules CARS 2D Computer Assisted Reaction Schemes allows you to draw molecules and reaction schemes with arrows reagents texts icons etc for slides publications etc CASA Computer Assisted Stereochemical Analysis al
34. ARS 3D When you switch from CARS 2D to CARS 3D the program tries to compute the 3D configuration of all the molecules on the screen up to a maximum of twelve The reverse process is also possible Obviously this is an enormous job the procedure therefore has its shortcomings 1 For cyclohexane rings the chair conformation is always used and the possibility of a boat is neglected 2 When no stereochemistry is indicated at the intersection of two rings the in ring bonds will be considered as equatorial 3 The transfer is not recommended for rings larger than 20 membered rings 4 The CARS 2D to CARS 3D transfer in this version is inoperative for bridged structures ex Bicyclo 2 2 1 etc in all from 5 to 10 of all molecules will give less than optimal results With the reverse function CARS 3D to CARS 2D this may be worse Since there are several degrees of freedom lost in the process of going from a tri dimensional space to a flat surface the results may be far less interesting chains may overlap queer distributions of alpha beta bonds may arise standard schemes for peptides and acyclic molecules are not always respected Note that this reverse process is also much slower 10 6 Molecule manipulation The Rotate Move and Scale options from CARS 2D are also available in CARS 3D In addition CARS 3D includes the Deep option for special three dimensional visualization Hydrogen to add or remove hydrogen atoms in 3 d
35. Axis 115 118 p Back 112 Background 34 Ball amp Stick 123 ball and stick 25 Batch 103 Batch Jobs 11 Bend 58 115 beta 31 55 bit planes 117 Bond 50 112 Bond Rot 121 Bonds 123 bonds distance 32 bonds width 32 Box 31 107 Branch functions 43 Build 52 112 28 N S 28 CAPS 6 27 Carbocyclic molecules 37 Carbon Numbered 31 CARS 2D 6 26 CARS 2D to CARS 3D 109 CARS 3D 7 26 CASA 6 26 CASA Commands 65 CD ROM 10 Chain functions 42 Change Password 26 Change Viewing Point 32 charges 29 ChemDraw CT 23 Chiron Interchange Format 126 Chiron Program 5 chiron 1 10 CHIRON_HOME 10 CIF 23 45 49 126 Clear 59 Cleave 50 Cleaved precursors 81 Cleaving 93 Clip 119 clip distance 32 Color 124 Color Preferences 34 Commercial 21 Common 80 Connectivity Table 28 CPK 123 Critical 94 CSSR 23 Current 118 current 16 18 46 Cyclic molecules 40 p D Amino Acids 51 Dash 50 Deep 114 Delete 56 103 Delete Hydrogens 113 Delete Lone Pair 113 Delete Molecule 20 Depth 31 124 Dotted line 32 Double 49 118 Draw 31 54 113 Draw3D 108 112 Drawing Options 31 Duplicate 52 f Enantiomeric 71 Enantiomeric 72 EPS 25 Exceed 12 Exclude All 18 Exit 73 104 124 eXodus 12 Export 23 126 Extended 70 Extra Menu 27 Extremity functions 41 EZ 68 Lp File
36. Draw3D to help you determine the orientation of the bonds proposed by the program as you draw the molecule Each projection can be displayed or eliminated individually using the Floor and Wall commands The usefulness of the projections becomes evident for moderately complex molecules With increasing complexity however the projected bonds may interfere resulting in a loss of viewing perspective The program offers the interesting capability to select the projection of an atom or a molecule when you have to identify one at any time For example if you want to delete an atom but the area is too crowded you can do it on the projection rather than the structure 10 107 10 4 Molecule drawing Draw and Undo these options remain the same as in CARS 2D Draw can only input molecules without perspective lying in a plane parallel to the screen See below for drawing in Draw3D Build Build options work exactly as in CARS 2D There are several set of templates in 3D and you can use your own template sets if you wish Use of the templates is highly recommended for drawing 3D structures First set of Templates s 3 gt Draw3D Draw3D is a semi automatic drawing system Start drawing by selecting Start then choosing starting point on the screen Draw3D will propose a series of possible bonds extending from this point they will appear dashed You can examine the different proposed bonds by selecting the Next
37. Find To begin the search for precursors to a target molecule When all parameters have been set indicate Find to start the search You can stop the search at any time by pressing the Stop button If you have indicated Critical Atoms their atom numbers will be displayed in color The specific part of the target molecule will be highlighted After indicating Find you will see a dialog which shows the updated searching information that is current database current file the number of precursor it has searched in the current file the number of precursors found up to date the score of the best found precursor After you get some hits use commands like RSP RSBC Place or Report to see the results 9 95 In Match mode the program will stop searching after it has found 200 precursors Chiral and Racemic mode the program will keep only the best 200 precursors RSP Rapid Scanning of Precursors To rapidly visualize the precursors that were found on the screen After the program finds precursors you can scan through them by selecting the RSP command When you indicate a point on the screen where all precursors will appear the following dialog will appear Previous 1 List Discard Current Discard Rest Done Cancel Help Press the First button to display the first non discarded precursor Press Previous to see the previous non discarded precursor Press the Next button to displa
38. Indicate Fischer then indicate each carbon atom of interest in sequence they will be numbered in color as you indicate them or simply indicate the first and last carbon atom note that in this mode the program will choose the shortest carbon chain When the desired atom chain has been selected indicate the Fischer command again Indicate a point in the work area where the Fischer projection is to start and a second one below the first where the projection is to end allow sufficient space depending on the length of the chain The Fischer projection will appear automatically Fischer projections of different parts of the molecule can be shown on the screen simultaneously by going through this process several times Fischer Fischer 16 17 18 OX 20 ox 22 23 24 Me 12 Me 25 13 Me 14 Me 27 AGLYCONE 15 Fischer Fischer 1 5 1 1 NH HN 2 4 sO M OH EE 5 N 1 XC 3 4 N o XC 2 ACIVICIN Figure 7 9 Extended To obtain an extended projection of any part of a molecule Indicate Extended specify the desired chain as with Fischer When the desired atom chain has been selected indicate the Extended command again Indicate the leftmost end of the zigzag chain in the work area where the extended projection will appear automatically To draw a rotamer of a molecule segment Indicate Reshape then specify the chain as with Fischer For every a
39. RSP Shapes e Draw steroid or eicosanoid shape Repeat as above e Select Find and ask for the precursors of your choice Use RSP to scan the matches found 8 87 e Start a search with Match All instead of Match Exact 8 9 Aromatic precursors The Chiron Program databases contains many aromatic and heteroaromatic precursors The program will only match an aromatic compound over an aromatic part of the target The program will also try to match an aromatic compound over a carbocyclic part of the target but it will lose a lot of points If you want to search such precursors then ask only for aromatic and lower the minimum score enough By default the program will not not try to match a aliphatic precursors to match on aromatic target If you want the program to allow that kind of match select the Allow Non Aromatic on Aromatic radio button in the Parameters Dialog To get aromatic hits you only have to ask for AROMATIC AROMATIC CONDENSED POLYAROMATIC HETEROAROMATIC HETEROAROMATIC CONDENSED or POLYHETEROAROMATIC files in the File option in CAPS Also in the COMBINATION file you will find examples of non aromatic compounds hydroaromatics Example of an aromatic precursor DL Dopa found by the program for the Morphine DL DOPA 97 Aldrich 10 216 4 DB COMMERCIAL F AROMATIC MORPHINE 72 216 P M 1 14 9 1 Figure 8 19 8 88 CAPS Command To search precursors for a target molecule load the molecule onto t
40. To retrieve the precursors found for each target use the Get command You can kill a job that is executing in batch by typing kill 4 where is the number of the job between square brackets which you should have noted when you type the command otherwise use the jobs command If you stop the job or if it was not completed you can send it again in batch and non completed jobs will be run again completed jobs will not be searched for 2 11 2 4 Chiron Program X Server The program may be run terminal or a personal computer like Macintosh or Real time module will not work on such terminals even if they support OpenGL To enable your personal computer to run the program you must have an X Server There are many software packages available that will do this We have tested the program on a Macintosh using eXodus from White Pine software Inc www wpine com On an IBM PC we used Exceed from Hummingbird Communications Ltd www hummingbird com Your personal computer will need to be networked since it must communicate with the Silicon Graphics computer where the program actually runs This connection may be set up in several ways but the most desirable approach is to have an Ethernet card on your personnal computer and to connect it to the same network as the host SGI computer Once you have connected your personnal computer to the network and installed the appropriate software
41. X Y end 14 X Double head 5 X ArrowKind I2 6 X color I2 1 100 characters planar 0 false 1 straight Put 0 for default A alpha 1 true 2 double Put 1 for default B beta 3 full head 4 equilibrium Appendix Icon Definition Format By icons we mean graphic objects included in the program which will enhance the quality of your reaction schemes For convenience the icons have been defined in an external file which allows you to draw more icons and include them in the program A icon def file format The icon definition file is located in the main directory of your Chiron program file system Its format is quite simple The only valid information on the first line of the file is an integer marking the number of icon definitions in the file do not forget to change this number if you add or delete definitions The actual definitions follow this first line there are no blank lines in the file Comments may be added at the end of every line but there may not be full comment lines B defining an icon An icon is defined in three steps 1 On the first line of the definition a letter determines the icon s structure its orientation and the meaning of its control points a Vertical icon is marked by V its first control point is its top extremity and its second control point is its bottom extremity Horizontal icon is marked by an its first control poi
42. ady exist You can add a new database to the main database by typing the correct password when prompted This option is only available when the Main Precursor file type is selected You can use the Current File menu item to change the file type Remove Database To remove the current database You will be asked for confirmation You cannot remove the Chiron and Commercial database New File To create a new file for molecules or precursors depending on the current User Molecule setting Type the name of the new file in the dialog The name must not already exist You can add a new file to the main database by typing the correct password when prompted Remove File To remove the current file You will be asked for confirmation You cannot remove original files which came with the program File List This command will list in a file the contents of the current molecule file with molecule names references etc An alphabetically ordered list will follow sorted according to the sub chain which begins with the first capital letters The program will ask you for a file name and for the number of the first and last molecules to list Scan Database Allows you to search in all active databases and all active files for molecules or precursors Select the parameters then click the Search button The program will search for molecules that satisfy all the parameters For example a search with the parameters specified in the Scan dialog picture
43. ailable for 3D gt 2D transfer Exceptions are in the case of bridged polycyclic and related structures 2 D drawing of peptides using symbolic notations The current version of the program depends heavily on pattern recognition Remember that it will only work with what you have drawn on the screen and with what is in its memory The program has great eyes but it doesn t have your instincts judgment intuition or experience In the final analysis you will have to decide what to do with the information that is presented to you on the screen The working examples and publications are good reference points 1 4 Structure of the manual This manual will introduce you to the program and how to best use it Part 2 explains how to run the program on your Silicon Graphics computer Part 3 describe the Menu items which are available from any module Parts 4 and 5 describe the CARS 2D module Part 4 contains a general description while Part 5 details each CARS 2D command and dialog Parts 6 and 7 describe the CASA module Part 6 contains a general description while Part 7 details each CASA command and dialog Parts 8 and 9 describe the CAPS module Part 8 contains a general description and details on how to best use the precursor search options Part 9 details each CAPS command and dialog Parts 10 and 11 describe the CARS 3D module Part 10 contains a general description while Part 11 details each CARS 3D command and dialog Part 12
44. an then decide the extent of regio and stereochemical convergence pharmacophore overlap and plan your chemistry accordingly i e modify your precursor chemically etc See Figure 8 16 for an example in which Monensin was entered as a target and Erythronolide A as a precursor All framework carbon atoms in erythronolide A were entered as essential atoms when it was saved The lactone ring oxygen and the substituents were not entered as essential Note the reshaping of the macrolide and the excellent functional stereochemical convergence Only one overlap combination is shown Figure 8 17 shows the reshaping of butaclamol and fentanyl into a Morphine perspective A direct application of the Match option could be found in a preliminary rapid survey of possible pharmacophores or structural mimics Thus one can search for a Match of precursors with a given target having a certain topology and complement of important functional groups This process can be considered as a pre selection of potential pharmacophore mimics Those precursors can then be subjected to a chemical modification program as well as to energy minimization A lot of time can be saved by first finding promising precursor structures using this simple protocol provided by The Chiron Program then moving on to more sophisticated methods You can rapidly draw a target shape without functionality just to see molecules adopt the same shape see example next page 8 86
45. are more than four atoms bonded to the asymmetric center the result can not be guaranteed The program will use the 4 heaviest atoms to determine the descriptor which is not always the right thing to do Draw sulfoxides with a single bond to the oxygen OH st Me Figure 7 7 EZ Defines olefin geometry Indicate EZ and the designations will appear next to the corresponding bond The priority of each ligand is found using the CIP rules as for RS 7 68 insert alpha or beta bonds to change the assignation of an already asigned atom Indicate R or S Point to the carbon atom for which you want stereochemistry The appropriate alpha or beta bond will be drawn Indicate R S to get R S designations as you specified next to asymmetric atoms OH R and S option Figure 7 8 Tree Draw a priority tree from the CIP rules The tree will stop expanding as soon as all of its branches are not equal to each other or when the spanning of the molecule is finished This option is very useful to learn and visualize the sequence rules To draw the tree just indicate the asymmetric center you want to see the priority tree After that place the tree by indicating its top and bottom left extremities All the branches will be sorted from left to right in decreasing order of precedence Presently this option works only with rule 1 higher atomic number precedes lower To obtain a Fischer projection for any part of a molecule
46. asterisk near the atom instead of an R or S You will also see a near the center if the positions in space of the three bonded atoms are too ambiguous to determine the R S descriptor correct topology but insufficient stereochemical information Go to the next chapter for a full explanation of the RS option and its implementation The asterisk and notation can be removed in CARS 2D using Delete in the Texts option OH OH OH R OH P NH 6 60 Figure 6 2 2 Place a structure with no stereochemical designation on the screen Select R or S and point to the desired atom the computer will insert alpha and beta bonds as appropriate 3 Load the Leukotriene precursor and ask for E Z Figure 6 3 4 Load Erythronolide A Select Fischer Select a sequence of carbon atoms or simply select the first and last carbon atoms The program will choose the shortest carbon chain between the two atoms Indicate Fischer again to terminate your selection At the program s request indicate two points on the screen along a vertical axis and the Fischer projection will appear Do the same again but reverse the order of the carbon atoms Note the upside down projections and a different idea for a synthetic precursor 5 Ask for an Extended projection for the segment of your choice Indicate the chain as with Fischer and Extended again to terminate your selection Indicate the left side of the pr
47. ate THIENAMYCIN 1R 2R 2 Amino 4 cyclohexene 1 carboxylic acid M S Kobayashi et al T L 25 2557 1984 DB CHIRON F CARBOCYCLIC BRANCHED 52 11 P M 7 7 6 8 Cleaved 52 11 P M 4 2 7 7 Cleaved and reshaped Figure 8 10 Annulate Extend O N X Annulate 10 Cleave Extend ALBOLIC ACID R 5 Methylbicyclo 3 3 0 oct 1 ene 3 6 dione D W Brooks et al JOC 52 2036 1987 DB CHIRON F POLYCARBOCYCLIC 60 59 P M 10 22 8 13 Cleaved 60 59 P M 4 6 10 22 Cleaved and reshaped Figure 8 11 Extend HIRSUTIC ACID 4S 6R 7R Bicyclo 3 2 0 4 carboxy 4 methyl 1 heptanone A E Greene et al JOC 50 3957 1985 DB CHIRON F POLYCARBOCYCLIC 73 13 P M 8 20 9 12 Cleaved Figure 8 12 8 82 Extend Annulate MEROQUINENE 1R 2R 2 Carboxymethyl 1 hydroxymethyl 4 cyclohexene M J B Jones et al JACS 104 4659 1982 DB CHIRON F CARBOCYCLIC BRANCHED 65 22 P M 7 2 9 6 Cleaved 65 22 P M 4 10 9 6 Cleaved and reshaped Figure 8 13 8 4 Working examples for cleaved and reshaped precursors Acivicin acyclic cleaves Select ACYCLIC 6 in File Select Acyclic Cleave in Parameters e Select Functions and choose Secondary Alcohol and Amine NHX e Find e Select the Place command and put precursor 1 and 2 on the screen With Transformation to get chemical transformations Thienamycin cyclic cleave Select CARBOCYCLIC BRANCHED in File Cl
48. axis that passes by both atoms If you twist within a ring the entire molecule will be rotated Axis to rotate a molecule in 3D around the axis formed by two atoms You must indicate the two atoms order is important and the molecule will rotate by Angle degrees around their axis Invert to invert the stereochemistry of an atom left becomes right and vice versa You can select Invert a second time to restore the previous position Newman to display a Newman projection along a designated bond Indicate two consecutive atoms and the molecule will be rotated in space and presented in a perspective where both atoms are superimposed The rest of the Rotate submenu is the same as in the CARS 2D menu 11 115 Part 12 Real Time Module Current 1 View Mono i Move Axis Clip Translate Scale Rotate Auto Rot Bond Rot Twist Shape Shade help Exit Quit The Real time module will allow you to manipulate a molecule in real time Real time refers to the fact that calculations for the manipulation and movement of molecules are fast enough to give the user an impression of smooth movement This module is most useful to see a molecule in movement or to rotate a molecule to the desired angle for a picture Most functions apply only to the current molecule see the Current command in this section The Shape and Shade command lets you change the way molecules are displayed You can easily learn the commands by
49. be NR Uer E ulcer Reade en ere goce 32 GTN EET 53 DAW ree nosci I mA eu An mc deben eI D s 54 Alpha Beta peren X 55 ATOTUS Ee bad en NR Nae LEE 55 ar IM 55 Hanc pac E E 55 Reshape otis eee ceat Synod sted e sete ede ed ye orte oet da ente E ted avs os endet beo vetro pede Ue pede eode o deese AN dox suis yee 56 Moye E E 56 Deletes UE E 56 OTOT N Uu T o o ea eum 57 oci M IR 58 C Tear xo DOOR ees Nas Eb aie ate eet e d e dA 59 DIL UTILI 60 CASA 60 6 1 Working examples for te pepe oe sees cb reip 60 Av WE Var eK Vetus ku DON OPI i Mrs 65 RS tnm n ni se ere nempe orta E EE waa Meteo nt sas bats ueteri a dates mei sse es sana betees 66 DLE 68 Rand Seien eer yet ler c repr Ere eee RT Ser E Ebr EP ERR ME 69 Dc 69 reste exe tab b arte te o trao cet Peta tu etes pe Pac De Eve iR Se eee SS 69 Extended LEE 70 Resliapes iiis e er shan RE HERE HC ERE REO eR RE PEE REP RE REEF ME ESEESE PSE 70
50. by products proprietary compounds etc with those of target structures In this manner you may discover potential pharmacophores structural mimics hence candidates for chemical modification and new uses for old compounds In this option only the carbon framework is matched without consideration of stereochemical overlap In Match All all atoms are accepted in matching operation In Match Exact carbon atoms are matched with carbon atoms and hetero atoms for hetero atoms ex N for N O S etc Be aware that if your parameters are not restrictive enough the program will very quickly find the maximum of 200 matches It is suggested you use the Single Precursor parameter in File to try to match only one precursor The All Atoms Specific Atoms parameter will also decrease the number of matches found You can see on the next page examples of chiral structural mimics and pharmacophore search 8 84 2 MONENSIN Target ERYTHRONOLIDE A SECO ACID Abbott F MATCH Match 9 P M 1 15 15 1 ERYTHRONOLIDE A SECO ACID Precursor Figure 8 16 13 Butaclamol DB USER F WORKING_ FILE Match 1 P M 1 8 14 1 HO D 4 FENTANYL i DB CHIRON F MATCH Match 3 P M 6 18 14 1 Figure 8 17 8 85 When Match mode all search parameters can be used except for Minimum Score Maximum Score since scores are given for matching precursors This command works by finding precursors with th
51. by turning them ON or OFF Precursor After selecting the Single Precursor item in the CAPS Search menu item enter the number of the precursor in the current database file you want to search for 9 90 Functions To select the functions that you may or may not want on a precursor d ACID COOX LACTONE The program will only try to match precursors that correspond to all functional groups you selected The more selective you are the faster the EI ALDEHYDE CHX search will be These groups can be anywhere in the precursor and not necessarily in the expected positions The program will not search for precursors which don t have the required functions The program must match the precursor before seeing if the functional group is in the right METHYL KETONE place The Functions command works the same way as the Function sub menu option in Scan menu but after selecting a precursor that matches all Ed ALCOHOL OX parameters it will try to match it on the target molecule PRIM ALCOHOL 4 Select Functions in CAPS then point to the functional groups you want once or don t want twice the screen You will get a or an to 2 the left of it If there is no Y or N in the toggle box like 22 then the functional group will not be considered and it may or may not be present Accept All Exclude All in the precursor accept all functional groups select Accept All aware that if you start a sear
52. ces of characters in texts and atom names in subscripts or superscripts digits following a letter or one of the or symbols will be written as subscripts With Subscript set OFF the user must specify the characters to be put in subscript or superscript himself using the special control characters and amp see the Atom menu for details on the use of these control characters Hydrogen to include methyls as Me and hydrogens next to atoms example OH NH By default hydrogens are included therefore all unfilled valencies are assumed to be occupied by bonds to hydrogen Drawing Options CARS 3D Foor Depth All Numbered see CARS 2D above Carbon Numbered Wall Hydrogen v No Number E Box Carbon Numbered see CARS 2D above No Number see CARS 2D above 2500 Point Floor to either display or remove the molecules reflections on the OK Help floor of the box Note that no reflections are drawn if the box is not active see Box Wall to either display or remove the molecules reflections on the left wall of the box Note that no projections are drawn if the box is not active see Box toggles the display of the CARS 3D box Depth to toggle the highlighting of molecules frontmost bonds 3 31 Hydrogen see CARS 2D above Perspective to modify the viewing distance from the box A large number r
53. ch all functions are memorized for the next search without exiting from CAPS So if you change your mind don t Done Reset forget to indicate Accept All and the new functional groups For example if you select Acid and Amine put a Xl to the left of both When you select Find the program will search only for Amino Acid precursors If you search in the ACYCLIC 6 file it will search only for acyclic amino acid precursors of length 6 If you select Carbocyclic the program will search only for carbocyclic amino acid precursors You can put an to the left of Alcohol it will then search for amino acid precursors that do not contain any alcohol groups You can use any combination of and and the program will only try to match precursors that correspond Specifying Acyclic Aldehyde and Polyol will most probably find carbohydrate precursors If you add Amine you will get aminodeoxy carbohydrate precursors If you ask instead for CH2 you will get deoxy carbohydrate precursors Specifying Carbocycle not branched and putting an to the left of CH2 will get you fully saturated polyol precursors such as Inositol 9 91 Parameters NN 100 Ea 1 100 5 Qu 2 220 Specific AllAtoms v SpecificAtoms Additonal 0 00 w ire Se Aromatic 4 Don t Allow Allow Non Aromatic on Aromatic Score This search parameter is to sp
54. ch can also be quite fast if you only have few precursors Also precursors are sometimes not properly numbered or well drawn so it would be a good idea to use the program to redraw and remember them To add your own main precursors database be sure your are in the Main Precursor file type by selecting the File Current menu item then create a new database by using the File DatabaseOperation New Database menu item When you use the Import menu item ask for automatic classification If you add your own precursors to The Chiron Program library use a meaningful reference so you can easily recognize your own precursors and index your own database You will find the Print From File command very useful it will print your precursor database on a PostScript printer using the same format as the precursor manual 4 45 CARS 2D Commands 4 p Ea 22 1 31 a The CARS 2D Computer Assisted Reaction Schemes palette window is mainly used to draw molecules and reaction schemes using Template Build Grid and Draw commands A description of the commands in their order of appearance in the menu follows on tet To include text on the screen for reaction schemes or titles A text has the following attributes the text itself the position on the screen a size a color and a justification All texts attr
55. command Bond command will convert the current proposed bond into a real one and a new set of proposed bonds will appear at the end of this bond you go along observe the perspective reflections which indicate the direction of the proposed bonds in space Draw3D also has a few options to append substituents modify proposed bonds and an Undo command Here are some guidelines for drawing with Draw3D Figure 10 3 1 Select Start to start drawing a branch Draw3D will ask you to choose a starting point 2 If you indicate an atom Draw3D will propose the first of a series of possible bonds that may be added to this atom always based on the tetrahedral geometry of an SP3 carbon If you indicate an unoccupied point in space Draw3D will respond by proposing the first of eight bonds lying in the plane of the screen from which you may start building the skeleton 3 You can now browse through the different proposed bonds by selecting Next Draw3D will display each proposed bond in turn Repeat until you obtain the one you want look at the reflections If you miss the bond keep on selecting Next it will come back 4 Once the bond you want is displayed select Bond Draw3D will redraw the proposed bond as real It will then move to the end of the new bond to propose another set of bonds If the other end of the new bond is near enough to another atom Draw3D will close the ring by connecting this bond to the atom Using thes
56. crease or decrease the size of all molecules on the screen After you Hel p One Mol to increase or decrease the size of a single molecule on the screen After you select this command select X Y or X amp Y and point to an atom of the desired molecule It will be scaled by the current scaling factor Rotate Angle This command will allow you to manipulate a molecule as if it were a plastic ball and stick model vis X Axis Y Axis Z Axis when you select one of these commands the program will rotate the molecule around the X Y or Z axis Mol to rotate all molecules on the screen by the specified angle Every molecule on the screen will be rotated texts and arrows will not move amen One Mol to rotate a single molecule on the screen by the specified angle If you have more than one molecule on the screen then indicate any atom of the molecule to rotate the molecule will rotate by the specified angle Bend to change an angle within a molecule You must indicate three consecutive atoms the appendage of the last one will be redrawn in order to Done Restore Hep Done Restore Hep Restore Heb Help get the desired angle between the atoms Don t forget to select an angle first Bending is not allowed within a ring Twist to pivot parts of a molecule s substructure around a specific bond You must indicate two consecutive atoms and the appendage of the second one will twist around the
57. creen It is possible to write parts of the text in superscript or subscript You can place the same text several times consecutively Get to get a text that is already on the screen and its attributes Indicate Get and the text you want to be the current one You can then use Place to put a copy of the current text to somewhere else or Modify to modify an existing text Modify allows you to change a text already on the screen by the current text To make corrections to a text that is on the screen first Get the text do your corrections or change a text s attributes indicate Modify and point to the text to be modified Move to move text to a new position on the screen Indicate the text to move and the new position The text will keep all its attributes Delete to delete text from the screen Size to change the size of a text that is already on the screen Color to change the color of a text When locating a text it will be of the default text color which is the color of Text in the Color dialog When you indicate Color and a text the text will become of the color of Text H You can toggle back to the default color by indicating the text another time If you change the default color for text it will not change the color for text on screen Size slider to change the current text size By default a text is of size 12 and the default font is Times You can change the current size between 1 and 128 so that every text you put on
58. cursors will be formed for segments of the target molecule that bear no asymmetric center While this may be regarded as wasteful in terms of chirality in the few cases that this is encountered the carbon framework of the precursor is well utilized Aromatic rings will appear in two perspectives because of a rotation around a single bond This may control the position of a substituent with regards to its overlap with the target PRECURSORS TARGET x x Me Me Me X match C match Higher score Lower score Figure 8 1 Here is the usual way to work with CAPS Enter the CAPS module with your target molecule by selecting the CAPS box in the Module menu You can then change some parameters and start a search by selecting Find Default parameters will make for a good search but will look at every precursor in every file trying to match them everywhere onto the target and the search will be very time consuming You can help the program find precursors faster by reducing the number of precursors to examine according to the type of precursor you want and possibly by specifying only part of the target to be matched against The time it takes to find precursors is directly proportional to the number of precursors it examines and to the number of atoms in the substructure of the target to be matched You can also use the Automatic File Selection which will select the appropriate files to search in For example if your target is a heterocycle a
59. describes the Real Time module It describes the module as a whole and then details each command and dialog Every molecule in this manual was created using the MacChiron program using the Print To File command then inserted into a word processor 1 8 1 5 Notation Throughout this manual the following conventions observed The program refers to The Chiron Program Button and menu item names are set in a different Typeface to highlight them nput from the user is set in boldface Program answers to the user are set in italics General program output is set in the Courier typeface CARS 2D CARS 3D CASA CAPS and REAL TIME are termed modules The following figure shows terms that are used in this manual to describe the graphic user interface Work Area Pulldown Menu Text Box Menu items Push Button Radio Buttons Option Menu Toggle Button BN NETT Main Window Palette Window 1 9 Installation and Execution Note If the new version 5 0 of the Chiron program is already installed you can go directly to Part 2 2 2 1 Installation The CD ROM you received contains the executable version of The Chiron Program and all the script and data files It is a complete system with two central databases and many users can be added to the system each with their own files files are archived in the CDROM sgi chiron5_0 tar file on the CD ROM To install the Chiron program ru
60. e 10 108 options it is possible to draw regular chains and some rings For others use the Template command see 7 below 5 To draw branch points just follow a chain to the end then as Draw3D is proposing bonds select Back Draw3D will backtrack and propose bonds for the last atom drawn that still has room for bonds From there you can continue drawing branches or backtracking Note however that backtracking will stop at the point where you last indicated Start 6 Adding substituents to a molecule can be done in two ways e Draw the skeleton and bonds then insert S H etc atoms from the Atom menu or use the right mouse button to access the atom popup menu as in CARS 2D e Draw the skeleton or chain using Start etc Insert O S and H atoms at the tip of the current proposed bond by selecting the correct atom name from the submenu and selecting Bond The bond will be made real with the proper substituent at its end and the program will backtrack to the previous atom on the chain as described earlier To return to skeleton building in the normal way select the C menu item 7 Input of regular shapes is quite easy with these options but shapes like 5 carbon rings are difficult Use the Template option As an alternative you can use the Twist L and Twist R commands Pivot the bond proposed by Draw3D around the previous bond by increments of 10 until you close the ring 10 5 Transferring molecules from CARS 2D to C
61. e precursor manual 15 per page You will be asked for the first and last molecules to print and for the number of the first page Odd and even numbered pages are printed correctly for double sided reproduction Print Select Printer to send the Postscript information directly on the printer using the command in the Command text box Select File to save the Postscript information on the file specified in the File text box Use the Browse button to change the file name Print Kind PostScript PostScript B amp S Select Postscript to print what is on the screen Select PostScript B amp S to produce molecule printouts that resemble the ball and stick molecular model PostScript B amp S has a parameter list allowing you to change atom and bond sizes and colors it also permits the printing of stereoscopic images Texts arrows and icons are not printed by PostScript B amp S PostScript B amp S is only available in CARS 3D Figure 3 4 EPS Format The graphic description generated by the program is standard with the Adobe 3 0 Encapsulated PostScript File EPSF format The EPSF format is a standard format for importing and exporting PostScript language files among applications in a variety of heterogeneous environments Typically the purpose of the EPS file is to be included in another PostScript language page description like PageMaker Microsoft Word ShowCase etc Options Allows you to specify the output exactly as you
62. e content of the SCHIRON user directory into your current working directory If you already have a user database created with a previous version of the program please enter into the chiron subdirectory before running the program Please note that old preferences are lost in the process of upgrading to The Chiron Program version 5 0 All users will have read only access to the main databases but can read and write to their own files initially there are less than 5 kb allocated per user database Users can modify the main database by typing in the correct password when the program prompts for it The person responsible for the program should modify the password after installation note the original encrypted chain HOME main mainpassword dat in case you forget the new one the default password for the program is in capital letters CHIRON 2 3 Batch Jobs Precursor searches may be done in batch mode after the search parameters have been selected Once all parameters are specified select Batch instead of Find You will have to enter a name for this job job is entered in a local queue You can put more than one job in this queue To start the search in background chiron b amp You will then see the list of jobs that are waiting After you indicate Batch you cannot remove the job from the queue in Chiron but you can do it by editing the filebatch dat file in your current working directory
63. e in degrees Stereo displays a static stereoscopic image of the molecule on the screen You can then visualize the molecule s 3D structure using stereoscopic mirrors The stereo image remains until you press Return This sub menu allows you to move the molecule along the Z axis that is going in and out of the screen plane All sends every molecule on the screen deeper using the current depth offset Watch the projections on the floor and the wall to evaluate the depth change One moves an entire molecule If there is only one molecule on the screen the program will move it automatically to its new position otherwise you will be asked to specify an atom of the desired molecule Atoms to change the depth of individual atoms leaving the rest of the molecule untouched Offset changes the current depth offset which you can see in the cursor scaling box Move Delete As in CARS 2D 11 114 To scale or all molecules along the Z or X Y Y axes The scaling factor is preset to 1 00 you can change it by indicating a point with the slider between 0 25 and 4 00 Factor X Y 2 to scale the molecule depthwise Watch the projections on the sides to see the effect X amp Y amp 7 to scale the molecule in all three directions thus preserving its proportions select this command select X Y or X amp Y molecules will be scaled by the Done current scaling factor All Mol to in
64. e same or lower number of essential carbons and other atoms as found in the target structure The idea here is that if there is a good match it is easier to extend the precursor chain than to shorten it Non essential atoms in a precursor will simply not match any segment of a target but will be used to compute the final score Acyclic precursors will match acyclic and cyclic targets in many ways Cyclic alicyclic aromatic precursors will match the corresponding cyclic portions of the target If there are any residual non essential atoms they ll either extend in different ways to match any remaining atoms in the target or dangle in space somewhere Branch points and ring junctions will exactly match equivalent parts of the molecule To become more familiar with this command try a few matches and scan over the hits with RSP Hetero atoms N S O etc can be considered as interchangeable in the Match Exact mode All atoms are interchangeable in the Match All mode even carbon with non carbon You can therefore make the match as restricted or as general as desired The designation of essential atoms in a precursor highlighted skeleton determines which atoms will be matched with the target structure Consideration should be given to the type of match i e searching for new synthetic uses or pharmacophore matching with known targets It is important that essential atoms in potential precursors be entered manually when being saved in
65. ecify the minimum and maximum score to get precursors Scores are given by the program based on the degree of framework functional and stereochemical convergence between the precursor and the target When the program finds a hit it will calculate a score and if this is higher than the minimum score and lower than the maximum then it will add this hit to the other precursors found Note that the search will not be faster if you are more selective for those parameters since the program must do all the work to see if the precursor is good enough to be kept Note that you can ask for a negative minimum score for precursors such as 100 in order to find precursors that may be quite difficult to use as starting materials Atom Number To specify the minimum and maximum number of atoms on a precursor skeleton Those two parameters allow you to change the minimum and maximum number of essential atoms of the precursor These are atoms that must match the target structure or substructure The portion of the precursor that 9 02 matches the target appears in a different color Essential atoms are numbered when they appear on the screen in the precursor manual For example if you ask for CARBOCYCLIC precursors with minimum atom number equal to 6 and maximum atom number to 6 you will get only cyclohexane rings without carbon branches If you ask the same in CARBOCYCLIC BRANCHED you may get a cyclopentane ring with a branch of 1 carbon atom or a cycl
66. educes the perspective just like a camera with a zoom while a small number increases the perspective camera with wide angle lens Change Viewing Point to change observer s viewing point Select this command then indicate a point that will become the new viewing point the small cross represents the current point The screen s contents will be redrawn in the new perspective This option is useful to enlarge or decrease the viewing surface of the wall or the floor to better see the projections Program Preferences Allows you to change program preferences Note Old Program Preferences are lost in the process of upgrading to The Chiron Program version 5 0 1 Default line width width for all lines except large lines 2 Large line width width for large lines 3 Atom font size font size for atom 4 Atom number font size font size for atom number 5 Input precision radius of the circle within which an atom is recognized 6 Atom clip distance bond clipping distance around an atom with a displayed name 7 Number Atom distance average distance from number to atom 8 Double bonds distance distance between lines in double bonds 9 Triple bonds distance distance between lines in triple bonds 10 Alpha bonds width width of the small side of the triangle in alpha bonds 11 Beta bonds width width of the small side of the triangle in beta bonds 12 Alpha bonds lines number of lines in alpha bonds 13
67. er is used to select the relative brightness of near objects compared to that of far objects If it is set to 0 all objects will be in the same color no depth cueing and if it set to the maximum the objects nearest to the far clipping plane will be in black Color to change the color of the molecule on the screen Standard the color of each atom will be the standard color for that element Oxygen red Nitrogen green etc User the color will be exactly the same as in the CARS 3D module Atom Color to modify the color index of any atom When you select this menu box the program will enter help mode and the next command you will select will be explained instead of being executed Exit the Real time module changes will take effect and the molecule s will reappear in CARS 3D as it appears when you exit 12 124 Quit the Real time module changes will be discarded the molecule will be restored as it was before entering this menu 12 125 Appendix Chiron Interchange Format The Chiron Interchange Format is used for the following purposes Moving several molecules from one file to another Moving molecules from your own file to the main database when new molecules are to be made available to everyone e To transfer molecules and precursors to and from any database you need to interface it To transfer molecules from one machine to another from a Macintosh to a SGI for example To move m
68. ert charges an atom For example O will be recognized as an oxygen with a positive charge O 1 will not be recognized Isotopes and lone pairs are taken into consideration by the procedure that assigns weights to atoms in the process of characterizing R and S asymmetric centers If the Subscript toggle button in the Drawing Option dialog is set to ON its default value all the digits that follow a letter or will automatically be written as subscripts Similarly all and signs at the end of a characters sequence will automatically be written as superscripts It is possible to force a substring of a text or atom name into subscript or superscript simply by using these three special characters enter superscript mode Q enter subscript mode amp return to normal display mode To include one of these characters as part of a text or atom name and not as control characters simply type it following an exclamation mark 1 Here are a few examples of texts that you might want to put on the screen and the strings you would have to type to produce these texts with Subscript ON and Subscript OFF Desired atom or text Subscript ON Subscript OFF 2 CH2COO CHQ2 amp COO 2 2 2 1 1 B la 10 4 mol 200C 10 4 amp mol 20 o amp C 10 4 amp mol 20 o amp C If you want an If you want an If you want an 3 29 Periodic Table To take a
69. et the number of the matching atom in the target Select PostScript to obtain a graphic listing containing the same information as in the Text Only option but also including the precursor image An asterisk indicates an asymmetric carbon in the target Select MDL SDfile to obtain a listing of the best combinations found List To 9 98 Select Printer to send the Postscript information directly on the printer specified in the Command text box Select File to save the Postscript information on the file specified in the File text box Use the Browse button to change the file name Here is an example of a Precursors PostScript graphic listing obtained after searching ACYCLIC 5 precursors for Acivicin 9 99 CHIRON 5 0 Precursor Search List 1999 12 31 Acivicin Search Parameters Matching Chiral Score 96 65 100 Atom 3 255 Asymmetric 1 100 Cleave No Cleave Similar Accepted More option Off Databases Chiron Commercial Files Acyclic 5 7 hits 6 discarded Acivicin T o Un QU o Az St T o T T o m O T N A G OH PRECURSOR 1 SCORE 80 Name 2S 3R 2 Amino 3 5 dihydroxy pentanoic acid Ref S Saito et al T L 26 5309 1985 Database CHIRON File ACYCLIC 5 6 Match P M 1 1 2 2 3 3 4 4 5 5 PRECURSOR 2 SCORE 73 Name 25 35 4
70. from achiral or racemic compounds Aromatic and heteroaromatic precursor search dentification of duplicate precursors using the Morgan algorithm Exact and diastereomer searches e Scanning option with function recognition name and reference search formula search etc Postscript output black amp white or color on PostScript printer An option is available for Postscript output of precursors 15 to a page as in the precursor manual Stereoscopic display of molecules both on the screen and on printouts Optional printing of molecules according to the ball and stick model on PostScript laser printers User control of screen colors for molecules atoms texts arrows Possibility of defining your own templates for drawing molecules Direct access files for faster file operations such as loading molecules Densely packed file format for molecule files that take up less disk space nteractive access to the periodic table of elements Absolute stereochemical notation assignments for asymmetric centers Optional onscreen display of the priority tree of the bond weigths used in the RS algorithm Generation of Fischer and Extended projection for molecules or segments Possibility of adding boxes brackets parenthesis and other graphic objects on reaction schemes Geometric embellishment of the molecule 1 7 Automatic transfer of molecule s 2D structure to 3D structure the reverse is also av
71. he screen enter the CAPS module select the search parameters and press Find You will find general information in the previous section This section will explain the CAPS commands in detail The File Functions and Parameters commands will allow you to specify search parameters Annulate L Glutamic acid Oppolzer s Choice ALPHA KAINIC ACID Ald 12 843 0 FZACYCLIC 5 63 4 1 6 5 10 Annulate Exiend Extend Modify 4R 5R 5 Hydroxymethyl 5 methyl exomethylene cyclopentane 4 acetic acid T Money et al CJC 63 3182 1985 56 34 P M 7 8 9 24 OPHIOBOLIN C Figure 9 1 m 2 me m Points 4 Loaddob ee 9 89 To specify the databases and files you want to search in Using File you can change the current database or file by pointing to the radio button to the left of the desired database or file name You can also turn the databases or files ON or OFF by pointing to the toggle button to the left of the database or file name If you only want to use a few files for example ACYCLIC 5 ACYCLIC 6 and ACYCLIC 7 PLUS it is faster to make one of them the current file to ask for Exclude All and finally to turn the other two back ON For more information about the file organization see the File Organization section in Part 34 Automatic File Selection The program will automatically select files to search into You can then add or remove files
72. he terminal screen A brief description of each follows Figure 10 2 shows examples of the box molecules and their reflections on the left wall and floor Me HO pa AVERMECTIN AGLYCONE Figure 10 2 10 106 To properly recognize a three dimensional molecule a reference background must be provided CARS 3D this function is fulfilled by the box Its role is threefold 1 The box helps you visualize a molecule s dimensions in space by offering reference objects shadows on the left wall and on the floor 2 It defines the limits of the work space offered by CARS 3D 3 Itrepresents the perspective in which the molecule will be displayed in 3D 10 3 The projection The Drawing Options menu offers three options to alter the box s appearance Box which toggles the box display Perspective which provides and controls the perspective effect and Change Viewing Point which allows you to change the observation point into the box thus changing your viewing angle on the molecule v All Numbered E Floor 1 Depth Carbon Numbered Wall Hydrogen E Box No Numbered Perspective 2500 Change Viewing Point Help The shadows of a molecule will appear left wall and on floor of box For most molecules a quick look at it and its shadows should reveal the position of its atoms This feature is most useful in
73. ibutes are saved in a file If the Subscript toggle button of the Drawing Options dialog is set ON all the digit sequences that follow a letter a bracket a parenthese or an accolade will be put in subscript Likewise all or signs that follow a letter or one of the aforementioned characters will be put in superscript they will be treated as charge signs To overrule this automatic behaviour turn OFF the Subscript toggle button and select the character sequences to be put in super subscript yourself using the control characters 9 and 4 See the Other item in the Atoms menu for details on the use of these control characters Current Text to enter text from the keyboard It is possible to write parts of the text in superscript or subscript See Other in the Atoms menu 5 46 Justification usually when you indicate the position of a text on the screen you do so by indicating the lower left corner of the first letter of the text However if you want the right side of a text to finish at an exact place on the screen you will have to move the text several times to get it correctly With this option you can indicate the relative position in the text on the screen The position of the point relative to the text is the same as the small circle in the following figure Middle Left Middle Center Middle Right ABCDEF ABGDEF ABCDEP Lower Left Lower Center Lower Right ABCDEF ABGDEF ABCDER Figure 5 1 Place to place the current text on the s
74. ick Exclude All then point the HETEROCYCLIC toggle button to make it active In Parameters dialog Select Cyclic Cleave Set Minimum Score to 50 Set Minimum Atom Number to 7 precursors with at least 7 skeleton atoms Set Minimum Asymmetric Center to 2 Find e Place found number 7 place it Reshaped and As Drawn 8 5 The More option This option allows you to see precursors which are good matches except for one or two unfavored transformations Ex oxidation of an unactivated carbon atom Normally such precursors will not be seen because of their very low score usually less than 0 However with the More option they can be seen and the Place command With Transformation option indicates the PROBLEM centers This allows the user to modify that precursor so as to make it a better matching one 8 83 examples of the More option PROBLEM NH Modify NH MODIF VA OX NH TN X OH OH X Me AA N O NU Annulate Annulate ACIVICIN L Norvaline L Norvaline Aldrich 85 163 9 DB COMMERCIAL F ACYCLIC 5 1383 7 P M 1 1 5 5 Aldrich 85 163 9 DB COMMERCIAL FZACYCLIC 5 45 7 P M 1 1 5 5 Figure 8 14 Deoxy OXID PROBLEM Extend Cleave Annulate Ketone precursor 65 1 P M 4 4 10 15 Cleaved and reshaped Figure 8 15 8 6 The Match command This command allows you to match structures in your database precursors intermediates
75. iewing Point 107 virtual colors 35 Visible Number 31 w Wall 31 107 Wedge 31 1 134 Width 49 Working example drawing molecules 43 Working example for Real Time 117 Working examples for CAPS 80 Working examples for CASA 60 Working examples for Cleaved and reshaped precursors 83 Working examples for Match 87 X X terminal 12 X RAY 23 X Server 12 Z Buffer 117 ZigZag 50 B 24 y 24 Acknowledgments We wish to thank many colleagues in industry academia and various institutes for their comments collaboration and encouragement in the realization of this project We also thank la Direction des infrastructures Technologiques d Enseignement et de Recherche Universit de Montr al for their collaboration The version 5 0 manual was edited by Bo Huang Benoit Larouche We thank Xinxia Cai and Bo Huang for updating the Chiron precursor database for version 5 0 We are greatly indebted to former members of the Chiron team for their technical input in the realization of this project Gilbert Gagnon Ani Glamyan Serge Meynard Maximilien Lincourt Eric Lauzon Luc Tr panier Bertrand Leboeuf Serge L ger Frangois Major Daniel Forest Daniel L veill and Kimberlee Potter Special thanks go to Luc Forest deceased May 1991 and Jonathan Franco 1 135 1 136
76. ill consider the target or its mirror image hence a lower score compared to the pure enantiomer Lastly achiral precursors will be found with a much lower score The Racemic parameter will compute a score without considering stereochemistry It may be used for racemic targets and it will search for racemic precursors as well as chiral and achiral ones The Matching parameter includes Match Exact where carbon atoms match other carbon atoms but not hetero atoms and Match All where all atoms can be interchanged With this parameter priority is given to framework superposition and it is useful for finding structural mimics and pharmacophore types of target molecules Match does not consider any score hence it is a different type of precursor search Cleaving This parameter specifies cleave and reshape operations If you use the default No Cleave parameter the program will not cleave any precursors and the match will proceed in the usual way If you specify Cyclic Cleave the program will cleave rings in a number of ways and will try to match the cleaved precursor in every possible perspective onto the target This is a very powerful option that allows you to find precursors that cannot be found easily with the human eye Depending of the difficulty of the cleave there will be a corresponding lowering of the score You can see examples in the previous chapter Cyclic Cleave will cleave vicinal diols olefins as well as ketones in the alpha
77. ill keep every precursor found NH NH OH HO 4 12 N O Acivicin Keep Remove Figure 9 2 Aromatic By default the program will not try to match a aliphatic precursors to match on aromatic target If you want the program to allow that kind of match select the Allow Non Aromatic on Aromatic radio button 9 94 Reshaping This parameter indicates the way in which precursors will be drawn with the RSP RSBC Report and Place With Transformation options This mode must be selected before calling any of the four options Reshape indicates that the precursor will be reshaped according to the contours of target s corresponding carbon skeleton As Drawn indicates that the precursor will be redrawn exactly as it was in the database Sorting The By Score mode allows you to see the precursors in decreasing scoring percentage The Common mode displays the precursors in alphabetical order After the program has found some precursors it will display them in decreasing order of score letting you see the best ones first by default If you want you can sort the list of precursors found by alphabetical order of name in order to get precursors that are found more than once for the same target back to back By placing common precursors together in the list you will be able to see if a precursor can be used to synthetize different parts of the target You can specify this mode before or after indicating
78. imensions Added hydrogens will replace free valencies Analyse to get some fundamental quantities for molecules like distance and angle between atoms You can also ask for a stereoscopic view of the molecule on the screen Deep Molecules in CARS 3D are in a box measuring 1000 units of distance along the X Y and Z axes Translation of the molecule on the X and Y axes is accomplished through Move Deep allows you to move the 10 109 molecule in the depthwise direction 7 axis by going In or Out of the screen by the specified step value You can change the depth of all molecules a single molecule or an atom Move moves the molecule in a plane parallel to the screen Delete works exactly as in CARS 2D but in CARS 3D you can select an object on the wall or on the floor shadows Scale CARS 3D s Scale has been generalized to allow scaling of the molecule along the X Y and or Z axes Rotate you can specify the axis along which you want the molecule to be rotated by indicating the X Y or Z box You will also find commands that will allow you to manipulate a molecule as if it were a plastic ball and stick model like Twist Invert Newman 45 degrees NH NH HO OH HO Rotate NH HN 2 og S HO Rotate Z Rotate X Figure 10 4 10 7 Energy minimized structures Molecules drawn with Chiron CARS 3D are not energy minimized However for most rings Template the
79. imum Score to 50 Click Done e Find RSP Forskolin Select File Point to the COMMERCIAL radio button then point to the CARBOCYCLIC BRANCHED radio button From the CAPS Search option menu select the Single Precursor item then enter 10 alpha Ionone in the Precursor text box You will now search only for a single precursor user s choice e In the Parameters dialog set the Minimum Score to 30 Select Find Use Place indicate With Transformation to display the results with transformations Morphine Select AROMATIC in File e In the Parameters dialog set the Minimum Score to 50 Set the Minimum Asymmetric Center to 0 Set the Maximum Asymmetric Center to 0 achiral precursors only e Find RSP 8 3 Cleaved and reshaped precursors The CAPS module has an option to cleave and reshape acyclic and cyclic precursors Diols double bonds and ketones are cleaved and the sites of the cleavage are replaced by an atom X which represents a given oxidation state The cleaved and reshaped precursor automatically adopts the shape of the carbon skeleton of the corresponding substructure in the target molecule To search in this mode one must select the Acyclic or Cyclic Cleave options It is possible to view the precursors Reshaped As Drawn individually The following are examples of cleaved and reshaped precursors Annulate 6 Extend x 1 2 X 4 Medio Cleave Annul
80. in space the program will propose one of a series of eight bonds To make Twist uf Twist Ri a real bond out of the proposed one select Bond You must choose Start before any other sub menu command Undo Point Bond to make a real bond out of a proposed one When in substituent adding mode it will put the substituent at the end of the bond and backtrack see Back Draw3D will automatically close the ring if it finds that the new bond has its extremity close enough Done _ to another atom Back to return to a previous atom where there is room for new bonds to be proposed This backwards search terminates upon reaching the atom where the last Start command began Next to browse through the various proposed bonds Everytime you select Next the next proposed bond in the sequence will be drawn and so on until you wrap around to the first proposed bond again Twist L Twist R to twist a proposed bond in increments of 10 degrees in opposite directions Twisting is not permitted for bonds connected to an atom with three other bonds Undo to remove the most recently added bond Draw3D mode it will remove the last bond you added since using Start Back or Bond In substituent adding mode Draw3D will then propose bonds for the atom where the deleted bond was attached 11 112 Draw To draws strictly planar molecules unless connecting structures of different depths It works the same way as in CARS 2D To draw in th
81. indicate any atom of the molecule you want to color 5 50 Peptide L Amino Acids D Amino Acids to toggle between L amino acids and D amino acids It is possible for instance to draw a peptide with D and L amino acids like D Ala L Phe D Lys Left Right Drawing Right Left Drawing in Left Right Drawing mode new peptides are drawn from left to right in Right Left Drawing mode from right to left Clear to remove the peptide sequence of amino acid symbols Build create a peptide sequence once the amino acid symbols have been selected Insert to insert one or more amino acids in existing peptide We recommend that you use this option only with molecules built with the peptide Build command Replace to replace a peptidic segment by another You will have to select two peptidic bonds before replacement they will be cleaved and the amino acids between them will be eliminated Replacing a segment by nothing deletes the original segment and welds the molecule To replace a segment that includes the first or last amino acid of a peptide Extend with the new segment and delete the useless amino acids afterwards Extend to add one or more amino acids at one end of a peptide You will have to select an atom from which the new segment will originate If you select a nitrogen atom it will become the last atom of the new segment if you select an oxygen it will become the first atom of the new segme
82. ing circle must be set at 1 6 0 and the arc must be drawn counterclockwise otherwise we would end up with the complementary 270 degrees There is no reason to stroke at this point and obviously none to fill as the accolade will remain an open path all the way so we continue without doing it and we indicate it by adding X X at the end of the segment s line which is now completed and looks like A 0 0 0 1666 0 1666 0 1666 0 K X X The next segment is a line going from 1 6 1 6 to 1 3 1 6 In PostScript it is always preferable to avoid breaking a path because the PS pen always traces the breaks and considers them valid parts of a path so we will begin this segment where the last one ended We will not stroke the path until the very last segment so the definition of this line is L 0 1666 0 1666 0 3333 0 1666 We skip the next few segments and reach the last one Obviously if we want anything at all to appear on the printouts we must call a STROKE after this last segment We decide that all of our accolades will always be black so we may set the color in the file If we wanted to allow accolades of different colors but otherwise absolutely identical we would mark it by inserting an s at the appropriate position and choose the colors at runtime Let s suppose that all of these accolades will always be drawn with 4 point lines The extension at the end of segment s definition will be X SOL 4 I
83. inin Figure 3 2 3 17 olecule Current File This command will let you select the current file as well as which files are active if you are working with Main Precursor files you will be able to select the current database as well as databases that are active if you are working with Molecule files you will also be able to select the current template file Accept All to select all databases or molecules Exclude All to exclude all molecules except the current one Select Template to select the current file as the template file There is a User template file and a Main template file If you press the Select Template button in you own file User you will be able to get those templates by selecting User in the Build dialog If you do it for Main files than you will get them with Main in the Build dialog Load To load a molecule or precursor from the current file and display it on the screen A list of what is in the current file will appear on the dialog Select the name of the molecule or precursor you want and it will appear on the screen erasing anything that was previously there Load Number To load a molecule or precursor from the current file and display it on the screen Type the number of the molecule or precursor you want in the text box then select the Load button The molecule or precursor will appear on the screen erasing anything that was previously there Add To add a molecule
84. is button you can change the axis of rotation with relation to the Z axis perpendicular to the screen Right Button The right button has no effect Bond Rot Bond Axis Rotation This option lets you rotate a molecule around the axis of a bond Left Button You can rotate the molecule automatically with this button While pressing the left button move the mouse up or down to rotate in any direction the speed of rotation will be calculated from the distance you move the mouse Middle Button Using the middle button you can rotate the molecule manually just like the Rotate command keep the mouse button pressed and move the mouse up or down to rotate in one or the other direction Right Button This button lets you select which bond the molecule will rotate around To select the bond simply point the mouse to any bond and push the right button the axis of rotation will now be parallel to this bond Twist This command lets you twist a part of the molecule around a bond This option works only with Mono View Left Button Using the left button you can twist the part of the molecule you selected before with the Right button Keep the mouse button pressed and move the mouse up or down to twist Middle Button The middle button has no effect Right Button 12 121 This button lets you select which bond the molecule will twist around To select the bond simply point the mouse to any bond and push the right button select the par
85. l Time from the Module menu to enter in the real time module By default you are in manual rotation Rotate Indicate a point anywhere on the screen and hold the left button move the mouse Point to the auto rotation command box Auto Rot and do the same Turn the molecule and use Translate to move the molecule Scale the molecule by holding the left button up and down Quit the Real Time module and load Huperzine A in the same file Return to Real Time and change the shape of the molecule by going in Shape In the Shapes section point on the Style option menu and select Ball amp Sticks Press Done and play with it Do the same after drawing your own molecule with CARS 3D Remember that the above 2D 3D options do not translate into energy minimized structure 12 117 12 3 Real Time Commands Current Molecule Control This command lets you change the current molecule Real Time options affect only the current molecule It is also possible to select all molecules at the same time by clicking until they are all highlighted or by pressing the space bar pressing space bar again will reset the current molecule to the one more recently selected Left Button Selects a new current molecule each time you press it Middle Button The middle button has no effect Right Button Let you select the current molecule by clicking one of its atoms or bonds Use this command to select the view mode you want Mono only the front view is
86. lecule Indicate the new position for that point and the molecule will reappear at the new position Arrow to move an arrow to a new position on the screen Point to an arrow and indicate a new position the arrow will be translated without rotating Text to move text to a new position on the screen Point to the desired text then indicate a new position and the text will move there Icon to move icon to a new position on the screen Point to the desired icon then indicate a new position and the icon will move there Frame to move everything within a frame Indicate two diagonally opposite corners of a frame an X will appear at the bottom left corner Indicate a new position for this corner of the frame Everything that is inside the frame will be moved according to the translation you ve indicated between the two points To delete atoms bonds molecules texts arrows and icons from the screen Atom to delete an atom or a molecule By default delete atom is selected If you wish to delete an atom simply point to it the atom and its corresponding bonds will be deleted Bond to delete bond from a molecule Point to the center of the bond to be deleted Atoms at the extremities of the deleted bond will remain except if the deleted Hel 5 56 bond was the last one connected Molecule to delete an entire molecule from the screen Indicate any atom of the molecule to be deleted Arrow to delete arrow
87. les differently i e 1 16 for target and 17 31 for target B otherwise you will be confused when atom numbers are referenced Once the program has found precursors you can examine the list of found precursors using the Report command you will have also the possibility to get the report on a file or sent to a printer The RSP command Rapid Scanning of Precursors is the best way to view the precursors that were found They will be presented in decreasing order of score so you will see the best one first according to the program s scoring system You will see the sub structure which was matched by the precursor in the molecule highlighting color When scanning through the precursors note the ones you prefer you can then place several on the screen with Place To use Place indicate the desired center of the precursor If a precursor is not well positioned you can Move it along with all of its associated information texts and arrows If With Transformation is asked for you ll need more room 8 77 CAPS using the Place command NH NH Cl OH XY Y di di d OH 2S 3R 2 Amino 3 4 dihydroxy butyric acid OH S Saito et al T L 26 5309 1985 FEACYCLIC 3 4 86 17 1 1 4 4 OH HO OH OH NH R R Tartaric acid Ald 25 138 0 FZACYCLIC 3 4 2 73 86 P M 1 1 4 4 2 NH OH OH OH 2 Amino 2 deoxy D mannose Comm FZACYCLIC 6 65 42 P M 1 1 5 5 Cleaved and re
88. ling the way it was before entering into this module Molecule rotation This manual rotation command lets you view the molecule at any angle This is the most useful command when it comes to manipulating the molecule Left Button Use the left button to rotate the molecule along an axis which is perpendicular to the direction you move the mouse The distance you move the mouse determines the amount of rotation If you want to change the direction of rotation it is best to release the button and press it again before moving in the other direction Middle Button The middle button lets you rotate the molecule along the Z axis While you press the button move the mouse up or down to turn the molecule counter clockwise or clockwise respectively note that this system provides an intuitive feeling if the cursor is to the right of the molecule being rotated Right Button The right button has no effect 12 120 Auto Rot Automatic rotation With this command you can give the molecule an automatic rotation in any direction and speed Left Button To change the axis of rotation for the current molecule While pressing the left button move the mouse in the direction you want to rotate The speed of the molecule will be evaluated using the distance between the position where you press the button and the position where you release it Middle Button With the left button you can only rotate along an axis that is parallel to the screen With th
89. look at the periodic table of elements It is possible to check some properties of an atom just by clicking on an atom box All the values have been taken from the Sargent Welch Scientific Company s periodic table Options Menu Drawing Options Program Preferences Color Preferences Drawing Options CARS 2D All Numbered to obtain atom numbers next to each atom You can Carbon Numbered add numbers more specifically with the Visible Number command in the Build dialog OK Help _ Wedge Subscript Draw E Hydrogen Carbon Numbered to obtain the molecule s carbon numbers No Number to erase all numbers on any atoms Wedge to change the display mode for alpha and beta bonds The default value OFF displays rectangular alpha beta bonds if set ON they will be take a triangular shape Note that rectangular beta bonds and wide bonds look quite alike be careful when using both on the same molecule Draw to change the drawing mode With Draw set to OFF the user draws by indicating the end points for every bond like for other programs you are used to it is not necessary to indicate each time you start a new bond or a new molecule With Draw set to ON drawing proceeds as described in the Draw command It is faster this way since there are less branch points in a molecule than atoms Subscript with Subscript set to ON the program will automatically write some sequen
90. lows you to obtain the following information on molecules R S absolute stereochemical assignment of asymmetric atoms E Z olefin geometry Fischer projections Extended projections Mirror images Chiral segment recognition IDENTICAL ENANTIOMERIC MESO CAPS Computer Assisted Precursor Selection allows you to select appropriate optically active starting materials chiral achiral or racemic for the synthesis of a given molecule new option RSBC allows you to scan the best precursor combinations for one or more targets Also the Match option will allow you to overlay a molecule onto the frame of another one in a more general way 1 6 CARS 3D 3D drawing and simulation allows you to draw and visualize molecules in 3 dimensions with simultaneous projection along two planes CASA and CAPS are both operative in 3D Real Time real time 3D molecule manipulation allows you to visualize molecules in 3 dimensions using real time rotation Various display options are available including dual views and stereoscopic viewing 1 3 Some of The Chiron Program features Here is a list of the program s most prominent features Capability to read and write chemical file formats MacroModel Sybyl mol amp mol2 MDL MOL file PDB SMD X Ray CSSR and ChemDraw Possibility of interfacing your own database with the program precursor and molecule database using The Chiron Program Interchange Format Precursor selection
91. n one of your files create a new one for them In the Current File dialog select the file you saved to be the current file with the radio button then click the Set Template button Choose User in Build to access your own templates You can also save a new set of templates for each user in a new Main file and access them with Main Template instead of User Template You can use any molecule as a template but all stereochemistry will be lost 5 52 You put templates on the screen by indicating an atom of a template X will appear the atom and then indicating the new position for that atom You can attach to molecules such as for spiro centers or place the template in an empty spot You may also connect a template along a bond Select the bond on the template an X will appear in the middle of the bond Now select the desired target bond on a molecule Lastly indicate a point anywhere on the side of the bond where you want to see the template appear since placement would otherwise be ambiguous Remember that templates are randomly numbered so use Renumber to change the numbering Quo Se The default set of templates with an example of their use Figure 5 4 User to use the molecules in the user molecule file system as templates Main to use the molecules in the main molecule file system as templates A hexagonal grid will appear on the screen its purpose is to help the use
92. n the Bourne shell script install sh directly from the CD CDROMy sgi install sh The xchiron program and its related files are organized as follow Structure of CHIRON_HOME directory CHIRON HOME xchiron chiron sh chiron 1 mdltochiron chiron main chiron user doc User molecule and Main molecule User s copies of Chiron Program precursor data files Initialization files the Chiron files manuals in PDF Configuration and preference files CHIRON COMMERCIAL Main precursor Main precursor from the litterature commercially available Figure 2 1 The installation script also installed a modified copy of the chiron sh script named chiron into a binary directory The chiron script sets the environment variable CHIRON HOME then start the HOME xchiron binary program You can also install the unformatted nroff manual page of the program CHIRON HOME chiron 1 into your local man directory 2 10 2 2 Running the program If you have indicated a binary directory included in your search path during the installation you can simply start the program by typing chiron otherwise you will have to specify the whole path as indicated by the installation script Individual users may be added automatically by the program if you run it in a directory where there is no user database If you answer Yes to a confirmation dialog the program will install a new user database by copying th
93. nctional groups from the Atoms Other menu item which are not unique atom symbols as Ac NHCbz etc are not recognized in CASA and CAPS They are to be used for reaction schemes or illustrations only Only true atomic symbols as defined in the periodic table may be used by CAPS CASA for chemical processing it is possible with the Atom Other menu item to enter Cl Mg F Br 4 40 Single functional groups recognized in CAPS In CAPS precursors are matched on the target molecule according to their framework The functional groups are then examined in order to determine the score The framework atoms are drawn in a different color than the rest of the molecule and they are numbered in the precursors manual Those framework atoms are absolutely essential to the matching process There are four types of functional group placements If an essential atom in the functional group is bonded to only one other essential atom it is an extremity If it is bonded to two other essential atoms then the function is set on a chain and its stereochemistry must be considered If it 15 bonded to three other essentials this atom 15 a branch point Finally if the essential atom in a functional group is a member of an aromatic ring it is in an aromatic function Here are the four categories with their corresponding functional groups If a functional group is not in this list it is considered a member of the other category Extremity functions OX
94. nd you only want heterocyclic precursors you can ask the program to search only in the HETEROCYCLIC file which contains about 1141 precursors making the search more than 14 times faster 16587 1141 As a second example if your target has about 30 carbons but you only ask for precursors for a 6 carbon chain within the structure the search will be more than 5 times faster If you ask only for the ACYCLIC 6 file about 455 precursors the search will be 36 times faster if you specified both parameters the search would be 5 x 36 180 times faster As you can see the more you narrow down the search the faster it is We suggest you use global searches in batch mode only 8 75 CAPS commands CAPS Flow chart of Specify Files Functions and Parameters RSP RSBC Place Transformation Rapid Rapid Text or Postscript Structure Scanning of Scanning of Precursors or Precursors Best Best Combinations Name Combinations Reference Name File Reference Score File Match Score Transformations Match Chemical Operations Figure 8 2 When searching for precursors using the CAPS module it is advisable to keep a few things in mind Remember that the program can only work with what is in its memory It cannot invent new precursors If the best precursor or the precursor you have in mind is not in the database it will obviously not be found On the other hand you can add new precursors if you wish and
95. ng an existing entry A list of what is in the current file will appear on the dialog Select the name of the molecule or precursor you want in the list The name and reference text box will be updated with the selected molecule You can use the paste facility to enter data a text box You will be asked for confirmation as you will permanently lose anything that was previously in the file at that location This option is not as fast as Save or Load because direct acces file has to be reorganized Replace Molecule Number To save a molecule or precursor on the screen in the current file replacing an existing entry the number of the molecule or precursor you want to replace in the number text box The name and reference text box will be updated with the selected molecule You can use the paste facility to enter data in a text box You will be asked for confirmation as you will permanently lose anything that was previously in the file at that location This option is not as fast as Save or Load because the direct access file has to be reorganized 3 19 Delete Molecule To delete entries permanently from the current file Select the molecules you want to delete Use the Shift key to extend the selection and the Control key to add remove a single item to the selection You will be asked for confirmation New Database To create a new database for precursors Type the name of the new database in the dialog The name must not alre
96. nimum carbon chain length for Enantiomeric and Identical is 4 since these options have to compare at least 2 asymmetric centers The minimum length for the Meso option is 5 carbons Identical This is an extension to the Identical option The program will accept the equivalency of two different but interconvertible functional groups such as a carbonyl and hydroxyl groups or the one way conversion of a hydroxy to a deoxy This may improve the chances of finding a common precursor Identical The C1 C6 and C1 C6 segments are identical superimposable NH Figure 7 11 Enantiomeric This is an extension to the Enantiomeric options The program will accept the equivalency of two different but interconvertible functional groups such as a carbonyl and hydroxyl groups This may improve the chances of finding a common precursor Show Segment To re obtain the dialog containing the list of segments Indicate Show Segment The list of segments will appear Point to the desired chain number 7 72 Mirror To obtain a mirror image of the molecule Indicate Mirror then the mirror image will immediately appear If you have more than one molecule you have to point to the desired molecule You can mirror even a Fischer projection or an extended projection Indicate Mirror again to go back to the original molecule NH NH CI Acivicin T xy Y Miro E dia di d N O O N Figure 7 12 To remove the
97. not completed you can send it again in batch and non completed jobs will be run again completed jobs will not be searched for To save the currently found precursors in a file After you have found precursors you can save them with the target and parameters in a file for future consultation You will have to give a name to this job You can recover it with Load Job just by going in CAPS without molecules and by entering the same name as in Load Job You can save more than one job if you want The program will not save discarded precursors in the file and all remaining precursors will be numbered consecutively The target and parameters are saved in a packed file into your current working directory with the name you indicated followed by the extension bat Precursors found will be saved in a packed file similarly named but with the get extension Those two files are the same as for a batch job You can delete them with the rm command Load Job To retrieve saved jobs or batch jobs when done When the batch job is completed you can get the results back by selecting Load Job and selecting the same job You can also retrieve a saved job by using the same name Note that any previous target and precursors on the screen will be lost With this command you can delete any precursor that was placed on the screen using Place RSP or RSBC Select Delete and point to an atom of the precursor to delete Text and arrows for With Transforma
98. ns ses e Heure n e 9 lg quM 10 Installation Execution i eorr ree nla Rai 10 2 1 Installati nz i E Re ins RE EE EET 10 2 2 Runnig the prOgram zc IIR tek POR VERS UE 11 2 3 BatchJobS Vo aoe cata e etse alias once ules ideae 11 24 The Chiron Progr m omn an X Serveti cio oen etes agus ses shea de ves P e eR ert m rte de PER E ee RE PIRE 12 2 5 rol IPIE 14 ESOS 15 Menu UV VERE EDDA ESTA QR E VELA NES 15 dieti emet eA aene iter EE 15 File organization tre yer en e ec ens eds Lo caen a yer ERE dus EE eo E EROR Dee eese Eyed a TED 15 C rrent Filey nas ede See bea be oon ck Ge se een SO 18 e E REN GNE PUE EUR GER ERE VAL E TET E ee 18 Load Nuimbet oett e et a Eo det dee eta 18 Addi Ie WRHuI eui eR WI IPM HUI 18 Peine E 19
99. nt and will be replaced by a nitrogen Delete to delete one or more amino acids You will have to select two peptidic bonds Upside Down to redraw a selected peptide upside down This may be useful if you are trying to draw a cyclic peptide however the terminal units have to be joined using the Draw Manual Reverse Manual Reverse of a selected peptide if it was drawn from left to right it will be redrawn from right to left Again this is mostly useful for the drawing of cyclic peptides Scrap to discard all changes made since entering the Peptide dialog Note For Proline the amide bond will be drawn in a cisoid geometry Use Twist in the Rotate dialog to transform it to transoid 5 51 HN y Me Twist 1 2 _ J OH 2 NH OH Figure 5 3 Duplicate Structure erase the drawing and numbering of schemes and molecules Visible Number Fr Duplicate Structure to duplicate a structure that is on the screen Select this command and specify an atom from the structure you want to duplicate Indicate a new position for the duplicated structure Visible Number by selecting this command you will be able to selectively display or hide the atom number of any atom on the screen by pointing to it You can select Reorder Table several atoms consecutively If you point to a numbered atom the number will disappear Original Numbering Renumber to renumber all some or one of the atoms in the molecule
100. nt is its left extremity and its second control point is its right extremity a Rectangular icon is marked an its first control point is its top left corner and its second control point is its bottom right corner Note that the control points of user defined icons may have completely different meanings but those indicated above represent a convenient and simple standard and we recommend that you follow it if at all possible 2 On the second line an integer indicates the number of segments in the definition a segment is a single line or circular arc 3 All the segments are then defined at the rate of one per line This line contains the following data character for the Segment A indicates an arc L indicates a line e The X and Y coordinates of the segment s starting point then those of the ending point e If the segment is an arc the X and Y coordinates of the arc s center of curve and a character indicating Clockwise C or Counterclockwise K rotation character indicating whether or not the segment is at the end of a path to be filled F indicates that the path is to be filled with a shade specified immediately after it in the definition that shade is defined by a number between 0 and 1 0 being black and 1 being white f indicates to fill the path with a shade defined at run time and thus variable among the instances of this icon X indicates that the path is not to be filled right now
101. ntrol To move the far and near clipping planes This lets you hide parts of the molecule s along the Z axis you can only see what is located between the far and near clipping planes Left Button While you press the left button you can push the two clipping planes farther back by moving the mouse up or bring them closer by moving the mouse down Middle Button While you press the middle button you can widen by moving the mouse up or shorten by moving the mouse down the clipping depth Right Button Lets you set the front and back clipping planes to be as close to each other as possible without hiding any part of any molecule Use this command to move the current molecule in any direction you want 12 119 Left Button While pressing the left button you can move the molecule along the screen s plane by moving the mouse in the desired direction Middle Button The middle button lets you tranlate the molecule along the Z axis When you move the mouse up the molecule will move away when you move the mouse down the molecule will move closer Right Button The right button has no effect Scaling control Lets you scale the molecule up by moving the mouse up and down by moving the mouse down There are no limitations for the size Left Button While pressing the left button you can change up or down the scaling Middle Button The middle button has no effect Right Button The right button lets you put the sca
102. obutane ring with a branch of 2 or two branches of 1 This option is useless for ACYCLIC 5 or ACYCLIC 6 files since all precursors in those files have exactly 5 and 6 essential atoms By default all precursors are searched Asymmetric Center To specify minimum and maximum number of asymmetric centers in a precursor You will be able to cut down in search time in a very significant manner and to get only those precursors with the desired number of asymmetric centers For example if you ask for a minimum of 3 asymmetric centers the program will search only for precursors that have at least 3 centers so the search will be faster and you will get a better choice of precursors Achiral precursors If you ask for a minimum of zero and a maximum of zero the program will search only for achiral precursors Matching To search for chiral racemic and achiral precursors based on a scoring system Matching shapes are also searched This parameter can be set to Chiral Racemic Match All or Match Exact by selecting the proper radio button In general searches will be conducted for chiral racemic and achiral precursors by matching carbon framework functional groups and stereochemistry Scores are given based on degree of convergence feasibility of transformations to be done and other parameters For an optically pure target chiral non racemic precursors will come out with higher scores if the convergence is good Racemic precursors w
103. ojection Scrap the Fischer and Extended projections Fischer Fischer Figure 6 4 6 Ask for Identical segments program will find segments that are identical superimposable and will display them as chains with the correct numbers Select chain number 1 and observe Select With Comment Underneath then select another chain in the dialog s list and finally point on the screen where you want the text to appear Use the Show Segment command to access the other chains The program will find relationships between differents molecules The C11 C14 and C23 C26 segments are identical superimposable Figure 6 5 6 62 MONENSIN C4 C8 C27 C23 segments are identical superimposable Figure 6 6 7 Ask for Enantiomeric then Meso as below You can ask for the above options with more than one molecule on the screen The program will find relationships between differents molecules including target molecules and precursors OH OH NH HO The C4 C12 segment is meso Figure 6 7 8 Select Reshape Follow the instructions on the message area you can reshape the molecule to adopt any desired orientation This can be useful for overlapping a structure over another by reshaping it You can enter CASA with the Grid to make reshaping a molecule easier 6 63 AMPHOTERICIN AGLYCONE Reshape example OH OH OH Figure 6 8 6 64 CASA Commands Fischer Fischer HO
104. olecules from one file to another first select the right file system and the correct current file Select Export from the File menu A file selection dialog will appear Select CIF from the option menu then specify the range of molecules or precursors you want To import your molecules change the file system and the current file then select the Import command from the File menu using the same file name and CIF file format If your university or company has a database of precursors or molecules and you want to use as targets or precursors in the program you can transfer them to the CIF format by writing a program to list your molecules in a text file using the format specified below Molecules or precursors are listed sequentially in the file Every field in the CIF format is a fixed length and is easily accessible with any language If some field does not mean anything to you use the default value To become more familiar with the format save a simple molecule in CIF format with Export in the File menu without color and compare the text with the picture 1 126 5 1 CIF example for Acivicin Figure A 1 000000000111111111122222222223333333333444444444455555555556666666666777777777 123456789012345678901234567890123456789012345678901234567890123456789012345678 Ol CHIRON 5 0 02 Acivicin 03 The reference 04 0 0 0 0510 06 11 07 10 0 0 000 00 344 658 500 10 10 9 2 0 RAK 08 20
105. on for rule 4 which is not implemented yet pn 5 Figure 7 4 rule 4 Like pair R R 5 5 precedes unlike pair R S S R M or P P precedes P or P M and R M or S P precedes R P or S M and M R or P S precedes M S or P R This rule is not implemented Ex Only partial R S assignments are made by the program for o HO M OH Figure 7 5 7 67 rule 5 precedes 5 precedes and precedes 5 Fully implemented You should be careful when you see that the program assigns pseudoasymmetric value small r and s since rule 4 is not implemented yet OH Me OH OH Me Me Me OH R f S Si S Es R S Me Correct assignment by CHIRON Wrong assignment by CHIRON the center can t be determined using rule 4 the center should be determined as S using rule 4 like pair S S precedes unlike pair R S Figure 7 6 Non carbon atom If the atom has 4 ligands the program will order those ligands correctly and will assign the right descriptors to them You should be careful when using structures that have asymmetric centers with bonded lone pairs In those cases you should implicitly draw the hydrogens because the hydrogens precede the lone pairs in the sequence rules and the only atom that can be omitted for the RS selection is the one located last in the order when assigning a descriptor to a carbon atom the hydrogens are often omitted If there
106. on to display the next combination Press Last to see the last combination Press Done to stop the scan and keep the information that was added on the screen or Cancel to remove it When the target molecule is somewhat large the structure may be compressed on the screen For better result we suggest you to use this command only with the target molecule on the screen 9 96 Hit 1 Overall Score 67 Overlap Index 82 Average Precursor Score 74 39 1 Oxaspiro 4 5 deca 6 9 diene 2 8 dione DB CHIRON F COMBINATION 322 Precursor List 53 Score 64 45 5 4 5 6 1 DB CHIRON F ACYCLIC 5 75 Precursor List 4 1 Score 88 90 Kijanolide p H dl 1R 2S 9S 10R 2 SO2Ph Me 8 oxo 1 2 10 5 6 7 8 9 octaHnaphthalene 1 COOEt DB CHIRON F POLYCARBOCYCLIC 448 Precursor List 27 Racemic Score 70 Figure 9 3 Place Transformation To place the precursor s that you wish to visualize on the screen Select Place Move the slider to the list number of the precursor you want to see and not its file number then indicate a point on the screen that correponds to the center of the precursor structure note the highlighted sub structure of the target which is already colored Select Reshaped to indicate that you want the precursor to be reshaped according to the contours of the target s corresponding substructure or As Drawn if you want the precursor to be redrawn exac
107. or precursor on the screen without erasing anything that is currently there A list of what is in the current file will appear on the dialog Select the name of the molecule or precursor you want Point to where you want to center the molecule precursor and it will appear on the screen 3 18 Add Number To add a molecule or precursor on the screen selected by number without erasing anything that is currently there Type the number of the molecule or precursor you want in the text box Point to where you want to center the molecule precursor and it will appear on the screen Save To save a molecule or precursor on the screen in the current file Any information obtained through CASA or CAPS will be saved along with the target for example a molecule with precursors Fischer projection R and S etc Type the name then the optional reference You should indicate if your precursor is racemic or not In such case the program will add dl automatically at the beginning of the name For precursors it will also indicate the overlapping structure by drawing a box around atoms You can select deselect an atom by clicking on it You should indicate the default selection if your are not too familiar with the CAPS way to search The molecule or precursor will be appended to the current file You can use the paste facility to enter data in a text box Replace Molecule To save a molecule or precursor on the screen in the current file replaci
108. order to give the structure flexibility for matching Thus for synthetic uses the carbon atoms in the main framework of the precursor should be essential as well as important hetero atoms which you feel should find counterparts in the target structure or those which are difficult to modify chemically for example a ring hetero atom For pharmacophore matching consider the specified atoms of the target as representing the pharmacophore Remember that those portions of the precursors that mimic potential targets should be entered as essential atoms when the precursor is saved You can consider the phenethylamine portion of a precursor as being essential in the search for analgesics 8 7 Matching a given structure Draw the target structure in the usual way Enter one or more structures as precursors in one of your precursor files giving them a name reference and essential skeleton as for ordinary synthetic precursors Go to CAPS with the target and activate the Match Exact match exact that is C for C and hetero atom for hetero atom only or Match All match all all atoms interchangeably mode by selecting the Match Exact radio button in the Parameters dialog When you ask for a match and you get a hit you ll observe when placing it on the screen a reshaping of the precursor framework as it adopts the shape of the target regardless of functional group overlap Sometimes functional groups also overlap in one combination or another You c
109. ostScript 25 Precursor 90 Precursor database 45 precursor manual 25 Preferences See Program Preferences Print 24 Print From 25 Print Kind 25 Print To 25 priority tree 69 Program Preferences 32 projection 107 Publications 6 Q Quit 26 125 R R 69 Rapid Scanning See RSP See RSP Real Time 7 12 27 116 Recover 33 Ref 22 Remove Database 20 Remove File 20 Renumber 52 Reorder Table 52 Replace Molecule 19 Replace Molecule Number 19 Report 98 Reshape 56 70 reshaped precursors 81 Reshaping 95 Rotate 58 115 120 RS 66 RSBC 96 RSP 96 S 28 69 Save 19 Save Job 103 Scale 57 115 120 Scan Database 20 Scan Diastereomer 22 Scan Double 23 Scan Exact 22 Score 92 Scrap 73 104 Search 22 Select Template 18 Sep 123 Shade 124 shadows 107 Shape 122 Shapes 123 Show Connectivity Table 28 Show Functions 27 Show Segment 72 Similar 94 Simple 50 SMD 23 Sorting 95 Specific 94 Start 112 Stereo 118 stereochemical assignments 66 stereochemistry 39 Stick 123 Stroke 49 subscript 29 31 46 superscript 29 46 Sybyl 23 Symbols 124 Synlib 23 T Template 34 44 52 term def 34 Text 34 46 Transformation 97 Translate 119 Tree 69 Troubleshooting 14 Twist 58 115 121 Twist L 112 Twist R 112 Undo 55 112 Update 55 user database 11 User Level 33 Valencies 43 View 118 V
110. position ex Baeyer Villiger reaction If you specify Acylic Cleave the program will cleave acyclic precursors or acyclic parts of cyclic precursors and will try to match those shortened precursors onto the target You should only use this mode if you think there might be a longer precursor that may match better after one extremity 15 cleaved 9 93 Specific To search precursors for a specific chain of atoms in the target molecule By default All Atoms means that all atoms are considered in the target i e the whole molecule When the Specific Atoms radio button is selected you can point to the first and last atoms to search precursors for that substructure If you want two substructures in different parts of the molecule start with the first atom and point to the last atom twice before resuming with the second substructure If you want to get All Atoms back indicate Atoms The program will not attempt to match other parts of the target molecule the search will therefore be faster Terminal substitution must be considered as part of the substructure in the search i e they must be indicated as specific also ex Forskolin The specific part of the target will be drawn in a different color during the search Critical To specify critical atoms and functional groups that have to be matched perfectly ex OH for OH etc With Critical Atoms parameter you point to an atom of the target generally a carbon and only precursors that
111. quire a much longer period of time if done visually even with the aid of molecular models The program will see a molecule in a multitude of perspectives and it will present the user with possibilities that may have otherwise eluded the human eye This is evident in CAPS where The program will decode the stereochemical and functional complexities of a target structure and relate them to structures or sub structures derived from more than 3100 optically active precursor molecules and more than 13400 racemic or achiral precursors The program consists of four modules CARS 2D Computer Assisted Reaction Schemes CASA Computer Assisted Stereochemical Analysis CAPS Computer Assisted Precursor Selection and CARS 3D 3D drawing and simulation Each module has working examples in this manual A fifth module which runs on Silicon Graphics computers allows manipulation of molecules in real time Part 12 of this manual explains the capabilities of this module The term Chiron is derived from chiral synthon See Total Synthesis of Natural Products The Chiron Approach S Hanessian Pergamon Press Oxford U K 1983 1 5 1 1 Chiron Program Publications Computer Assisted Perception of Simularity Using the Chiron Program A Powerful Tool for the Analysis and Prediction of Biogenetic Patterns Stephen Hanessian Maurizio Botta Benoit Larouche and Ani Boyaroglu J Chem Inf Comput Sci Vol 32 No 6 pp 718 72
112. r To find identical precursors in the same way as Exact including diastereomeric precursors that have the same framework with one or more different asymmetric centers The figure below demonstrates what is found when you indicate Diastereoisomers for 2 Amino 2 Deoxy D ALTROSE 3 22 OH NH OH NH O DIASTEREOMER OPTION NAAN OH OH 2 Amino 2 deoxy D allose 2 Amino 2 deoxy D glucose OH NH OH NH i OH OH 2 Amino 2 deoxy D galactose 2 Amino 2 deoxy D mannose Figure 3 3 Scan Double This command will search for duplicates in a precursor file It will look into all active databases and files and compare all pairs one by one to see if a structure appears twice It uses the Morgan name of all molecules that are already saved in the file and compares them The result will appear in a text dialog Warning The program may not recognize subtle differences in highly symmetrical molecules So verify the structure of duplicated molecule before deleting anything Even if there is only a little difference like a protecting group OMe instead of OH it will be considered different It will find every duplicated molecule whichever way they are drawn and numbered Import Export To import or export molecules from to other chemical file formats CIF MacroModel MDL MOLfile Sybyl mol amp mol2 Synlib PDB SMD X RAY CSSR and ChemDraw CT The program supports two way transfer of
113. r draw molecules Every point you indicate will be moved to the nearest grid point except when you try to select an atom bond or text You can remove the grid by selecting Grid again Note that the grid is active even outside the hexagon along the same imaginary pattern 5 53 AGLYCONE Figure 5 5 Draw Along with the Alpha Beta and Templates commands this command is used to draw the carbon framework of molecules Note The maximum number of atoms on the screen is 255 excluding not explicitly drawn hydrogens To begin drawing on an empty screen indicate Draw and the position of the first atom Indicate the position of next atoms in the main chain By default all atoms created are carbons until you change them The program will always add a bond between the new atom you are creating and the previous one except for the first atom you indicate after Draw So you must indicate Draw to start a new branch and the atom you want to attach to The carbons will be numbered in the order they are entered in You can change this numbering with Renumber in the Build menu All bonds are assumed to be occupied by unspecified hydrogens Hydrogens need never be drawn except for clarity stereochemistry at ring junctions etc Double and triple bonds can be drawn by activating the second point two or three consecutive times or by going back on a bond After you indicate Update the molecule will be redrawn Remember to inser
114. raw several arrows one after the other Move to move arrows on the screen You will have to indicate any point of the arrow to let the program know which arrow you want to move Then indicate the new position The arrow will be translated without rotating so that the point that you selected on the arrow will now be at the point you indicated to select the new position Move One to move only one extremity of an arrow Indicate an extremity then indicate its new position The other end will not move Delete to delete arrows from the screen Color to change the color of an arrow the screen to the Arrow H color Select it again to return to the Arrow color See the Options Color Preferences menu item 5 48 Icons To add various graphic figures to reaction schemes Display box to select the current icon among the available icons we have included brackets accolades boxes plain shaded and round and parentheses Furthermore you can define your own icons see Appendix B for details Double to draw paired icons Linear icons anything except a box may be at least as useful as pairs of mirror image icons as they may be by themselves This option allows the automatic creation of these pairs of icons at draw time if Double is ON In that case you will be prompted for a third control point which will indicate the distance between the twin icons With boxes this has no effect whatsoever If you decide to de
115. rawing mechanism and manipulation of bonds and atoms in space CARS 3D was implemented to offer an alternative way to enter molecules with complex or ambiguous two dimensional alpha beta representations such as bridged structures It can also be used in conjunction with precursor search analysis as offered by CASA and CAPS In CAPS framework overlap will be achieved with the correct precursors however the substituents may be somewhat off plane since the precursor molecules were entered in the CARS 2D mode CARS 3D INPUT MANIPULATION Draw Move Draw3D Rotate 2D gt 3D Twist Build Deep File Delete Atom Scale Detach O N C S H Figure 10 1 10 105 10 1 Entering CARS 3D Entering CARS 3D is done by selecting the CARS 3D item in the Module menu The CARS 3D menu will appear and the program will try to compute a suitable 3D configuration for the molecules on the screen see 10 5 for details You may return to CARS 2D by selecting the CARS 2D option and the program will try to build a good 2D representation for the 3D molecules which may or may not have been transferred from CARS 2D in the first place including alpha and beta bonds where necessary to preserve the molecule s stereochemistry You may also go directly to CASA or CAPS by selecting their respective menu boxes 10 2 Molecule representation We have included some features to help in the recognition of three dimensional molecules on a flat surface such as t
116. re 8 9 8 2 Working examples for CAPS After a molecule has been drawn on the screen or loaded from a file using the CARS menu move it to the top left hand corner of the screen For the following examples load the target molecules from the Main Molecule file TARGET select the CAPS command select parameters as specified and press Find Acivicin Select the File command On the File section of the dialog select the radio button to the left of ACYCLIC 4 then click on the Exclude All button Click OK You now have only one active file Select Find When done use RSP to scan through the found precursors Thienamycin Select File On File dialog select the radio button to the left of HETEROCYCLIC then click on Exclude All Select OK You now have only one active file e Select Functions and point to Secondary Alcohol and Methyl to get a Y on the left of both Click Done e Select Parameters then set Minimum Score to 50 Click Done Select Find Use RSP when done 8 80 Avermectin Go to File and point to the ACYCLIC 5 radio button Click Exclude All then select the toggle button to the left of ACYCLIC 6 to accept it Click Done You now have only two active files e Select Parameters Select the Specific Atoms and point to atoms 23 and 28 upper right Click OK on the Specific Atom dialog Set the Minimum Asymmetric Center to 2 to get precursors which have at least 2 asymmetric centers Set the Min
117. ree dimensions use Draw3D Atoms Undo Update As in CARS 2D Hydrogen Add Hydrogens to add hydrogen atoms to the molecule in 3 dimensions Hydrogens will replace invisible free valencies The molecules resulting from this option are not minimized but they make a good starting point for minimization on another program such as MacroModel or Sybyl You can remove the newly added hydrogens with the Delete Hydrogens command Delete Hydrogens to delete all hydrogens from the molecule on the screen Delete Lone Pair to delete all lone pairs from the molecule on the screen All Molecule to add hygrogens to or delete hydrogens from all molecules on the screen One Molecule to add hygrogens to or delete hydrogens from a single molecule on the screen Figure 11 2 11 113 Distance to obtain the distance between two atoms in a molecule Note that the box s width is 1000 It will also give you a distance in A 5 taking into account the average of the C C bonds in your molecule Coordinates to get an atom s coordinates X Y Z in the box The origin of the box is at rearmost bottom left corner The width of the box is 1000 in all directions The X axis is horizontal the Y axis is vertical and the Z axis is perpendicular to the screen pointing outwards Angle gives you the angle formed by two consecutive bonds You will be asked to select three consecutive atoms the program will then give you the angl
118. rm stereochemical analysis on your molecule CASA is capable of handling 2D and 3D molecules Note that individual R and S options for assigning alpha and beta bonds as well as Extended projections and the Reshape option are not supported for three dimensional molecules Selecting Exit from the CASA menu will bring you back to the previous module 3 26 CAPS To enter the CAPS module from where you can search for precursors for your molecules CAPS is capable of analyzing 2D and 3D molecules and matching them with 2D or 3D precursors You can search for 2D or 3D precursors and they will be presented in 3D using Place RSP and RSBC The scoring is the same if the target is correctly entered in 3D Selecting Exit from the CAPS menu will bring you back to the previous module Real Time To enter the Real time module which allows you to rotate molecules in real time and manipulate them as you want Presently this command works only on a Silicon Graphics Inc workstation See Part 12 for details Molecular Composition Show Functions Show Connectivity Table Molecular Composition To obtain the molecular formula molecular weight and elemental composition of the molecule on the screen You can also get the molecular weight and composition of any molecule by typing its formula on the Molecular Formula text box CIOH22O03N The atomic weights are obtained from the periodic table The result can be written into a file or prin
119. rrows on the screen Practice drawing more elaborate molecules ERYTHRONOLIDE A ne Figure 4 13 Drawing using Build templates and the Grid Make sure you are in CARS 2D Select the Build command Select Templates in the Build dialog and draw a structure by selecting an atom of a template then the desired position for that atom select another set of templates by chosing Main or User Try out the Duplicate Structure Renumber commands 1 Use the Draw command for bonds double bonds etc remember the numbering of atoms follows their drawing order Atom numbering can be changed with the Renumber command in the Build dialog When you want to start anew branch on your molecule you must select the Draw command again To draw a separate molecule you must select the Draw command and proceed 4 44 2 Use the Alpha and Beta commands to specify stereochemical assignments all alpha or beta bonds be included in sequence if there are more than one of each 3 Place all the required atoms by selecting them from the Atom menu C H O N S or by entering them via the Atom Other menu item Atoms are changed simply by pointing to the bond extremity where you wish the atom to be Similar atoms can be entered in sequence for example all oxygens in the molecule Remember that hydrogens NH2 etc are automatically added as are methyl groups By default an atom is a carbon unless you specify it as a hetero atom 4 To specif
120. s from the screen Point anywhere on the arrow to be deleted Text to delete text from the screen Point anywhere on the text to be deleted To delete just one part of a text use Modify in theText dialog Icon to delete icons from the screen Point anywhere on the icon to be deleted and you will be asked to confirm Frame to delete everything within a frame atoms texts arrows icons Indicate Frame followed by the two diagonally opposite corners on the screen where a rectangle will appear Indicate a point inside the frame to confirm or outside the frame to abort the operation and everything inside the rectangle will disappear Delete frame Example Example Figure 5 7 To scale one or all molecules along the X Y or X and Y axes The scaling factor is preset to 1 00 you can change it by indicating a point with the slider between 0 25 and 4 00 to scale horizontally preserving the height of the molecule Y to scale vertically preserving the width of the molecule X amp Y to scale the molecule in both directions at the same time keeping the proportions of the molecule which is what you will want most of the time Done He All Mol to increase or decrease the size of all molecules on the screen After you select this command select X Y or X amp Y All molecules will be scaled by the current scaling factor One Mol to increase or decrease the size of a single molecule on the screen After yo
121. sed to draw the atom This is used along with the number of lines Line 4 Line to change the number of circles used to draw the atom The number of lines Line tells you how many circles there are on the sphere and the number of points Points is the number of points in each circle It is better to have the same number in Line and Points to get the impression of a regular surface Bonds to change the way bonds are displayed Radius to set the radius of every bonds Points to change the number of points used to draw the atom This is used along with the number of lines Line 4 Line to change the number of circles used to draw the bond to change the internal separation between two lines of a double or a triple bond The number of lines Line tells you how many circles there are on the sphere and the number of points Points is the number of points in each circle It is better to have the same number in Line and Points to get the impression of a regular surface Labels to select how each atom s letters are displayed 12 123 Plain no letters are displayed Symbols the atom s symbol is displayed Symbols amp Numbers the atom s symbol and number are displayed Symbols amp H the atom s symbol with hydrogens extension are displayed Symbols H amp Numbers the atom s symbol with hydrogens extension and number are displayed Depth Difference for Depth Cueing this paramet
122. seuss sate 106 10 3 The projection e eerte ieee qe rite gestes ye ete eroe ety epe deste Uo ge Put er e ero gi 107 10 4 Molecule drawing sssi eere erc ER 108 10 5 Transferring molecules from CARS 2D to CARS 3D men hen he ee rennen 109 10 6 Molecule manipulation 1 2 rers teer ee Sese epe or ues geb ENO EET de rh To pe Pete s Ye qi 109 10 7 Energy minimized structures E rrr epe POE re pese Ete a Pop rete p Er 110 TA rr r M 111 CARS 3D a 111 ext BONS senza toa ents cesta at 112 Inr EE 112 Draw e eR eii alate Seale NN d MU bou die Ln bee 112 113 Atoms Undo Update eer IR to PETER 113 113 Analyze ER ERSTE PIRE 114
123. sh the screen 1 Using an xterm Launch Exceed Client Wizard e Fill up the name of your SGI workstation in the Host text box then specify SGI IRIX for Host_Type e Select Xterm and use default values for the Application and Parameter text box e Fill your username and password for your account on the SGI then click the Run button or continue to create a shortcut e Start The Chiron Program with the usual command 2 13 2 Directly starting The Chiron Program 3 Edit the file exceed_path user Stdappdb txt and add the following line in the SGI IRIX section 4 SG RIX Chiron fehiron path chiron where chiron_path chiron is the chiron startup script on your SGI computer Proceed like for 1 but select the Chiron popup menu item instead of XTerm Using a different X Server If you use an X server that we have not tested it will probably work correctly Changing some server settings may fix a problem that you may encounter 2 5 Troubleshooting The program has been thoroughly tested and will seldom crash even if we have made many modifications in the program to make it easier to use and X11 Motif complient If it does try first to see if anything simple could have caused the crash a quota exceeded or a file privilege problem for example if you cannot solve the problem and it appears unrelated to your specific setup send an email to The Chiron Program development team or send a FAX Describe the type of
124. shaped L Vinyl glycine FEACYCLIC 3 4 S Hanessian et al T L 25 1425 1984 65 23 P M 1 1 3 3 Figure 8 4 CAPS using the Place command With Transformation yo OH ZL Oxid ACIVICIN 2 Amino 2 deoxy D mannose Comm F ACYCLIC 6 65 1t 42 P M 1 1 5 5 Cleaved and reshaped Figure 8 5 8 78 Other CAPS examples Me OH PUNCTATIN A J Am Chem Soc 109 3017 1987 Me Me OH 17 18 FORSKOLIN J Am Chem Soc 110 3672 1988 COMPACTIN CX Annulate uM Branch 8S 8 Methyl 4 9 hydrindene 1 5 dione Hajos diketone Z Hajos et al Org Syn 63 26 1984 DB CHIRON FZPOLYCARBOCYCLIC 77 17 P M 10 10 9 3 Paquette s Choice Figure 8 6 B h Annulate md alpha Ionone Aldrich I 1 240 9 DB COMMERCIAL F CARBOCYCLIC BRANCHED 85 10 P M 7 18 13 16 Corey s choice Figure 8 7 3R 5S 3 Hydroxy 5 6 epoxy hexanoic acid Y Guindon et al T L 26 1185 1985 DB CHIRON F ACYCLIC 6 91 57 P M 1 1 6 6 Figure 8 8 8 79 CAPS with the Common precursor option 2S 3R 2 Hydroxy 3 methyl succinic acid K Mori et al Tet 36 87 1980 DB CHIRON F ACYCLIC 4 78 33 P M 1 14 4 11 OH AVERMECTIN AGLYCONE 2S 3R 2 Hydroxy 3 methyl succinic acid K Mori et al Tet 36 87 1980 DB CHIRON F ACYCLIC 4 65 33 1 26 4 23 Figu
125. sign your own icons be careful the Double option is effective with all linear icons even if in your case it is unsuitable Draw to add the current icon to the reaction scheme You will be prompted for two control points for boxes they are the top left and bottom right corners and for other pre defined objects they are the extremities User defined icons may have completely different control points Fill 1 00 Stroke 0 00 Move to translate an icon screen without altering its shape or its Done Default orientation Delete to remove an icon from the reaction scheme Fill Stroke Width the icon dialog has been designed as an enhancement for reaction schemes and therefore for molecules printouts These three options have no effect on the screen they only influence PostScript printouts Fill changes the interior shade of objects Stroke the line shade and Width the line width Modifications to these values only influences icons created afterwards icons created before remember their old colors and line widths This allows you to create a pair of black brackets change Stroke to 0 8 light gray 0 being black and 1 being white and add a light gray box to the same scheme The default values are white for Fill black for Stroke and 2 point for Width Note The CIF format does not save information about icons 5 49 This dialog allows you to put different types of bonds on the
126. t all extra atoms and functional groups before you update otherwise all extremities will become methyls To facilitate the drawing of rings and long chains Template in Build and Grid can be used You can change the drawing mode in the Drawing Options menu item Then you will have to indicate every time both extremities of every bond which is time consuming for long chains but more practical if you have a lot of branch points 5 54 Alpha Beta To indicate stereochemistry with a hashed line or solid wedge representing an alpha or beta bond respectively Draw the alpha or beta bond by indicating the origin and the apex of the bond the hashed or solid wedge will immediately appear Alpha beta bonds be drawn in sequence without reactivation You have to reactivate when switching from one to the other however The program can display alpha and beta bonds as wedges or rods toggle ge between these modes use the Drawing Options dialog in the Options menu Be careful when using wide bonds and rod shaped alpha beta bonds on the same molecule since it would be easy to mistake the wide bonds for beta bonds OH SENSE T NH NH Figure 5 6 To include the current atoms or functions in a molecule To change the current atom see the Atom menu Used to erase bonds that have been drawn with Draw The last bond drawn will be erased first You can erase double and triple bonds step by step You can contin
127. t are recognized by the program they are available in the aromatic template set 4 38 Figure 4 3 4 3 Stereochemical depiction of bonds The stereochemical orientation of single bonds substituents ring junctures etc should be specified using alpha or beta bonds Unassigned stereochemistry will not be recognized by the program or it may consider both possibilities Alpha and beta bonds have a direction point the wedge away from the originating carbon atom Bonds should always originate from a carbon atom toward other atoms Acyclic molecules Show one stereodescriptor in the case of a single substituent or two descriptors for tertiary centers The shorter chain should be regarded as a substituent Me NH N gt OH Me dnd K NH 0 Figure 4 4 4 39 Cyclic molecules All of the following are recognized Figure 4 5 4 4 Rules and comments on functional groups Protective groups are not considered by the CAPS module For example Moss HN Me OH NH Ox NX Me P Me Pp Me P Figure 4 6 Substituents should be entered as above with bonds separating each atom and not as OMe COOH COX The important aspect that is recognized is the alpha and beta stereochemistry of the substituents For stereochemistry to be recognized in CASA and CAPS all functional groups as well as stereochemical designation alpha beta must be drawn using the CARS 2D module Fu
128. t are registered trademarks of Adobe Systems Incorporated e Apple LaserWriter Macintosh QuickDraw are registered trademarks of Apple Computer Inc e Exceed is a registered trademark of Hummingbird Communications Ltd eXodus 15 a registered trademark of White Pine Software Inc IRIX and ShowCase are trademarks of Silicon Graphics MacroModel is a trademark of Columbia University REACCS ISIS and MACCS are trademarks of Molecular Design Limited e SYBYL is a trademark of Tripos Inc e SYNLIB is a trademark of Smith Kline amp French Laboratories Inc TEKTRONIX is a registered trademark of Tektronix Inc UNIX is a trademark of AT amp T Bell Laboratories Microsoft Word is a registered trademark of Microsoft Corporation Table of Contents PART E T AME 5 Foreword ie are x e S rhe NI AES e ESTEE TATUS 5 1 1 The Chiron Program Publications eee cient dade eee eere s ede en ae e cddbelsucduedtevccedacesdsesat 6 1 2 Overyiew of the modules d eere ve D ve ee xe gees ve eiae oer ea ere eee ib EIN TR NER E a 6 1 3 Some of The Chiron Program features 2 nhe rennen rna 7 1 4 Structure of the manual ie rete deett da e Nee deeds 8 DS Notatio
129. t is now time to present the whole definition If there were no accolades in ICON DEF we could add our definition at the end of the file using any available editor Always remember to change the integer on the first line of the file when you add definitions otherwise the program will not read the new ones The complete definition iS optional comments permitted at the end of every line 0 0 1666 0 1666 0 1666 OK X X 1666 0 1666 0 3333 0 1666 X X 23333 0 1606 0 5 0 3333 0 3333 0 3333 X X 5 0 3333 0 6666 0 1666 0 6666 0 1666 C X X 6666 0 1666 0 8333 0 1666 X X 0 8333 0 1666 1 0 0 8333 0 K X S 0 0 L 4 lt Ce O uo 1 129 1 130 29 amp amp 29 29 l 29 lal 24 24 24 1 1 Atom 50 1 Bond 50 2 2D to 3D 109 L Accept All 18 Achiral precursors 93 Acyclic molecules 37 39 Add 18 Add Hydrogens 113 Add Number 19 Adding precursor See Precursor database Additional 94 alicyclic molecules 37 Atoms 50 Bonds 50 Numbered 31 alpha 31 55 Alpha lines 32 Aromatic 94 Aromatic compounds 38 Aromatic functions 42 Aromatic precursors 88 Arrow 34 48 50 arrow head length 32 arrow head width 32 Asymmetric Center 93 Atom 34 Atom Color 124 Atom Menu 28 Atom number 31 32 34 52 92 Atoms 55 123 Auto Rot 121 1 131 Automatic File Selection 90
130. t menu you ll see when you start the program is CARS 2D menu which allows you to draw structures Using the mouse select the Draw command Move to the middle of the screen and draw a cyclohexane by going clockwise or counterclockwise Each time you go to the next carbon point you ll leave bond behind you Atoms will be numbered in the order you draw them and by default all atoms will be carbon atoms until you change them explicitly Now select the Alpha command and draw an alpha bond somewhere the structure Do the same with Beta Now select the Atom O menu item and insert an oxygen OH at the end of the alpha bond Select the Update menu box to redraw everything correctly The structure will be erased and will then reappear looking something like this OH ys Figure 4 11 4 43 You can also use the Shape command to reshapes molecules according to ideal bond lengths and angles Note that the hydrogens were added automatically When a bond is left with no substituents it will be considered to be amethyl Try out Delete To delete an atom or bond you must point at it When you draw a molecule you should always select the Draw command when you want to interrupt the sequence of lines bonds To draw another molecule on the screen select Draw and proceed as above Now draw L Proline next to the previous structure OH Figure 4 12 Try out the Texts and Arrows commands to add texts and a
131. t of the bond closest to the part of the molecule that is to be twisted This menu will allow you to change the drawing parameters There are 4 sections in this dialog Shapes Atoms Bonds and Labels 12 122 Shapes Style allow you to load predefined sets of parameters You can choose predefined set of parameters by selecting the desired item in the Style option menu Plain simple line representation as in CARS 3D CPK each atom will be represented as a shaded sphere The bonds are not drawn Ball amp Stick the molecule is displayed in a manner similar to a ball and stick model with shaded bonds and atoms Stick the molecule is displayed in a manner similar to the ball and stick model with shaded bonds and atoms The atom radius are the same as the bond s radius Old reset all parameters as they were when you entered the Real Time module Load to load a previously saved set of parameters Save to save the current set of parameters Note If you use the CPK model you have to be sure to set the back and front clipping plane as near as possible to the molecule use right button of the Clip option Atoms lets you change the way atoms are displayed Radius to set the radius of carbon atoms The value you enter is in the same range as 3D coordinates The radius for other elements will be calculated from this radius and from the Van der Waals radius of each atom Points to change the number of points u
132. ted Show Functions This option will show you functionalities in the molecule on the screen Those functionalities are the same as the ones you have to specify with Function when you select the Scan Database and CAPS Function command So if you are not sure if some special cases are included in one functionality then you can try it with this option For example if you draw the following molecule then the program will show you NH 9 Y ACID COOX LACTONE EPOXIDE ALDEHYDE CHX HALOGEN KETONE METHYLENE METHYL KETONE Y C BRANCH Y ALCOHOL OX Y ALKENE PRIM ALCOHOL SUBST ALKENE Y SEC ALCOHOL TERM ALKENE TER ALCOHOL ALKYNE DIOL POLYOL Y TERM ALKYNE ACETAL OO SS ORGANOMETALLIC Y METHYL PHOSPHONATE PRIM METHYL PHOSPHINE 3 27 Y SEC METHYL THIOL TER METHYL SULFIDE Y AMINE NHX SULFOXIDE Y PRIM AMINE SULFONE SEC AMINE Y CH2 TER AMINE Y PHENYL FUNCT NITRILE Y PHENOL PhOX AMIDE CONHX LACTAM ANILINE PhNX NITRO NITROSO TOLUENE PhMe ETHER Figure 3 5 Show Connectivity Table To obtain a connectivity table for a molecule on the screen The result can be written into a file or printed OH OH N O Thienamycin Acivicin Formula C11H1604N2S Formula C5H703N2C1 Molecular Weight 272 318 Molecular Weight 178 574 Atom Number 18 Atom Number 11 LX xc 132
133. the screen will use the closest font depending of the kind of terminal you have Even if the size is discontinuous to the font the real continuous value is remembered for a text and you will get the exact size on the printer even if you cannot see the difference on the screen You will also get more precise text size if you save for example your molecule in a file and load it on another terminal that has more fonts 5 47 Arrows s 1 Double E Straight Draw Move Using the Straight option Move One Figure 5 2 Delete Color Display box by indicating this button you will change the current arrow type see it change You can get simple arrow double line arrow full arrow head and equilibrium arrow Done Help Double to draw two headed arrow The arrow at left will be updated to get two heads You can double head any kind of arrow Equilibrium arrows always have two heads if double is OFF the equilibrium arrow will be drawn with one of its components half as long as the other and if it is ON both components will have the same length To draw move and delete arrows on the screen Straight this button allows you to draw arrows horizontally or vertically easily When you indicate the tip of the arrow the program will align it on a vertical or horizontal line Draw to draw an arrow You will have to indicate the end and the tip of the arrow inside the work area You can d
134. tion that are linked to this precursor will be deleted along with it Note that you will not be able to delete a precursors added by the RSP or RSBC commands without first closing the RSP or RSBC dialog 9 103 Move To move a precursor previously placed on the screen Select Move and an atom of the precursor to move Indicate the new position and the structrure will move according to this translation along with texts and arrows that were placed with it To delete all precursors from the screen leaving only the target After you indicate Scrap the target will reappear alone on the screen You can then place other precursors on the screen or continue with another search To exit from CAPS and return to CARS 2D or CARS 3D module 9 104 CARS 3D The problem of representing a three dimensional object on a flat computer screen is a difficult one Two major obstacles must be overcome namely loss of information on the positions of atoms and cluttering up of the screen with information that prevents the user from easily recognizing the structure We have devised some artifacts which help to simulate depth and perspective This is achieved by enclosing the molecule in a box and by projecting its shadows on the walls and floor of the box Selective highlighting of the frontmost bonds is possible CARS 3D has most of the features of CARS 2D but it also offers additional possibilities for molecule input such as a semi automatic d
135. tly as it was in the database 9 97 Check the With Transformation toggle button to have chemical transformations appear as keywords for a given precursor You must check the toggle box before indicating a point on the screen then you must indicate the positions of chemical messages around specified target atoms Keep in mind that there is text under the structure However if there is not enough room the program will bring the structure back inside the work area where you can move it using the Move command or delete it with the Delete command to delete all precursors use Scrap To obtain a listing of all the precursors or best combinations found for the target on the screen This information can be either viewed on a text window saved to a file or printed You can obtain the information in text format or a PostScript graphic listing containing the target molecule and all the precursors found Report Kind Select Precursors to obtain a listing of the precursors found for the target on the screen Select Best Combinations to obtain a listing of the best combinations found Output Kind Select Text Only to obtain a text For every hit the precursor hit number score name and reference of the precursor and its file name with precursor number in this file are given On the last line you will get information about the matched atoms in the chains of precursor P and molecule M For all essential atoms of the precursor you will g
136. to modify a color setting select the appropriate radio button object then select the color box you want for that object Object Molecule Atom Text Arrow already on the screen and saved in file will keep their colors Molecule the default color for new molecules After you change this index any new molecules you draw will be drawn in this color Molecule H the default color for molecule highlighting This color will be used for new precursor skeletons for Identical Enantiomeric and Meso chains and when you color bonds with All Bonds and 1 Bond in the Bonds dialog Atom the default color for atoms After you change this index any new atoms you draw will be drawn in this color Atom H the highlight color for atoms you select with the All Atoms and 1 Atom buttons in the Bonds dialog Arrow the default color for arrows Arrow H the highlight color for arrows when you select them with the Color command in the Arrow dialog Text default color for text R and S will be of this color Text H highlight color for text you select with the Color command in the Text dialog Number default color for atom numbers 3 34 Background the background color Grid the color used for the grid We suggest you use a dark color similar to the default dark blue to clearly see the molecules you draw over it which are in the Molecule color Template the color used for templates in CARS 2D and CARS 3D Save allows you to sa
137. tom of the selected chain indicate the new position in an empty part of the work area you will be prompted by atom number It can be useful to bring the Grid in CASA in order to reshape the molecule in a nice looking way Identical To locate identical superimposable segments in any given molecule or between two different molecules or precursors See the Meso command below Example of the Identical options The C3 C7 and C9 C13 segments are identical superimposable ERYTHRONOLIDE A Figure 7 10 Enantiomeric To locate enantiomeric non superimposable segments in a molecule See the Meso command below Meso To locate Meso plane of symmetry segments in a given molecule Indicate Identical Enantiomeric or Meso a dialog containing a list of chiral segments will appear if the molecule contains such segments Choose a chiral segment from the list The chiral segment will be projected over the molecule in a different color and with large lines and all the carbon atoms included will be numbered An arrowhead will also be drawn except for Meso indicating the direction You can change the highlight color by changing the Molecule H index in the CARS Color sub menu If you want the text describing the chiral segment click on the With Comment Underneath toggle box of the dialog and the text will appear when you indicate a point on the screen To reobtain the dialog containing the list of segments indicate Show Segment The mi
138. u select this command select X Y or X amp Y and point to an atom of the desired molecule It will be scaled by the current scaling factor 5 57 HN HN H N HN NH NH NH NH O O 2 Scale Y Scale X Scale XY Figure 5 8 Rotate To rotate molecules and perform other similar manipulations You can specify the angle by indicating the angle value with the slider All Mol to rotate all molecules on the screen by the specified angle Every molecule on the screen will be rotated texts and arrows will not move One Mol to rotate a single molecule on the screen by the specified angle If you have more than one molecule on the screen then indicate any atom of the molecule to rotate the molecule will rotate by the specified angle Bend to change the angle between two bonds First specify the desired angle then select Bend and three consecutive atoms The angle between the three atoms will be set to the new value by moving the appendage of the third atom H N 45 degrees 90 degrees Figure 5 9 Twist to twist part of a molecule that lies in the plane of the screen in 2D It will twist all atoms that are connected to the second atom you indicate by 180 degrees along the axis that passes through the atoms you indicated Note that it doesn t make sense to twist within a ring 5 58 Second atom First atom Twist Figure 5 10 Flip to flip the molecule horizontall
139. ue to draw after Undo without indicating Draw again but you have to indicate the atom to attach to Note Undo works only with Draw and Reshape To redraw all objects on the screen This option reshapes molecules according to ideal bond lengths and angles Rings will be drawn as regular polygons all bonds with the possible exception of those involving a hydrogen will be normalized to the same length etc If necessary alpha and beta bonds will be interchanged to maintain the original stereochemistry Acyclic chains will be reshaped to an extended zig zag horizontal form See section 10 5 for exceptions and limitations Molecules that cause problems with the 2D to 3D transfer will usually give poor results here Note You can return to the original molecule with the Undo command Move To move atoms molecules texts arrows and icons on the screen Atom to move a single atom of a molecule Point to the atom that is to be moved then indicate the new position the atom and its bonds will move to the new position If you move the atom too far you will be asked to confirm since almost every time the user actually wants to move the entire molecule All to move everything that is on the screen atoms molecules texts arrow and icon Indicate any point on the screen then the new position for this point Those two points specify an offset that will be added to everything on the screen Molecule point to any atom of a mo
140. ule on the screen such as in a reaction scheme they will all be saved as a single item On The Chiron Program CD ROM there will already be some files you cannot delete You can add files to all file systems and delete files if you wish You can see the list of files by using the Current File command in the File menu after you select the desired file system with Molecule Precursor and User Main 3 15 For each of the 4 file types there is a single current file which is the one you will Load from and Save in etc If the current file is not the right one you can change it by selecting the proper radio button to the left of every file name in the Current File dialog Also each of the non current files can be specified as ON or OFF by selecting the toggle box MM to the left of every file name This toggle is used for two purposes the scanning commands in Scan Database and precursor searches In both cases the program will travel from file to file considering only the files that are ON and skipping files that are OFF During a precursor search the program will search for precursors only in files that are ON The Scan option will look at and select only molecules or precursors in those files In this version the Main Precursor files are divided into databases This organization gives you the possibility of adding your own Main Precursors databases without modifying the databases that comes with the program You can have a maximum of 20 databases
141. umber of steps The precursors are depicted as basic structures without protective groups or extra substituents even if they were reported as derivatives in the original publication For example all sugars are entered as acyclic aldehydo forms rather than furanose or pyranose forms Azido or cyano groups are arbitrarily considered as amino groups in the corresponding precursors amino sugars Lactones may also be entered as the corresponding free acids The naming of the precursors follows standard everyday nomenclature and not CA nomenclature in some cases It is felt that for the purposes of the program the names are easily recognized as such They could be changed if desired to adapt to current CA or IUPAC policy Naming compound presently does not allow numbering like 3a 4H In such cases numbering will be continuous 8 74 8 1 CAPS overview Generally the program will adjust the shape of the precursor carbon framework to best overlap with that of the target However stereochemical information R S etc as well as precursor selection is best obtained on flat hexagonal etc or extended zig zag type structures and not chair or boat forms unless the chair forms are not heavily substituted particularly at the indented carbon atoms In general concave centers should be avoided such as concave carbons in a chair form In such cases draw the molecule using CARS 3D and proceed as usual In some cases pre
142. ve the current color setup Load allows you to load a previously saved object color setup For coloring bonds see the Bonds commands in the CARS 2D menu The Chiron Program virtual colors Index RGB color Lightness Color name 0 0 0 0 0 BLACK 1 255 0 0 76 RED 2 0 255 0 150 3 255 255 0 227 YELLOW 4 0 0 255 28 BLUE 5 255 255 105 6 Q 255 255 178 CYAN 7 255 255 2255 255 WHITE 8 255 150 255 193 MAUVE 9 0 140 0 83 DARK GREEN 10 60 130 255 123 SKY BLUE 11 0 120 120 84 BLUE GRAY 12 255 128 0 152 ORANGE 1 3 45 255 140 179 TURQUOISE 14 140 140 140 140 GRAY 15 50 170 0 115 MEDIUM GREEN 16 215 160 0 159 OCHRE 17 225 145 165 171 LIGHT PINK 18 185 70 60 103 BROWN 19 200 255 25 213 YELLOW GREEN 20 230 110 90 144 LIGHT BROWN 21 33 96 197 88 MEDIUM BLUE 22 225 125 250 169 LILAC 23 250 140 65 165 LIGHT ORANGE 24 90 190 150 156 BLUE GREEN 25 252 185 148 201 FLESH 26 50 210 179 159 LIGHT BLUE GREEN 27 255 255 128 241 LIGHT YELLOW 28 255 128 128 66 SALMON 29 255 65 20 7 DARK ORANGE 30 255 40 170 9 PINK 31 0 0 110 2 DARK BLUE 3 35 Help Menu On Version To displays the program s design credits On Context To obtain a brief explanation for each command Select On Context and the comand you wish to have information on 3 36 CARS 2D With this module you can draw molecules up to
143. visible results of the RS R S Tree Fischer Extend Identical Enantiomeric and Meso options Indicate Scrap the screen will be updated leaving only the original target molecule s To exit from CASA and return to CARS 2D or CARS 3D module 5 In this version 16587 precursors of these 3130 are optically active are provided with the program with molecular formula reference or source 1927 are racemic compounds and 11530 are achiral precursors They are divided into 21 files according to their framework shape There is also a file for match type precursors Here is the list of the precursor files refer to the precursor manual ACYCLIC 3 ACYCLIC 4 ACYCLIC 5 ACYCLIC 6 ACYCLIC 7 PLUS AROMATIC AROMATIC CONDENSED CARBOCYCLIC CARBOCYCLIC BRANCHED 10 CARBOCYCLIC BRIGED 11 COMBINATION 12 HETEROAROMATIC 13 HETEROAROMATIC CONDENSED 14 HETEROCYCLIC 15 MACROCYCLIC 16 MATCH 17 NUCLEOSIDE 18 POLYAROMATIC 19 POLYCARBOCYCLIC 20 POLYHETEROCY CLIC 21 STEROID The list of precursors which is representative rather than exhaustive has been gathered from four sources 1 commercial products 2 products of microbiological or enzymatic processes 90 e e or d e designated by the letter M after the name 3 products obtained by resolution designated by R 4 products obtainable by chemical manipulation of readily available compounds using a reasonable n
144. want it The first five options are common to PostScript and PostScript B amp S These parameters are saved when you exit the program The font index is the following 1 Times Roman 2 Times Italic 3 Courier 3 25 4 Helvetica 5 Bookman Light 6 AvantGarde Book 7 NewCenturySchlbk Roman 8 Palatino Roman 9 ZapfChancery Mediumltalic Change Password This command will allow you to modify the main database access password you correctly type the old password you will be asked to type in the new password you will then be asked to re type it to make sure that you have not made any typing mistakes If the two spellings match the password will be changed to the one you typed The default password when you receive the CDROM is CHIRON in capital letters Quit This command will allow you to quit The Chiron Program Module Menu CARS 2D CARS 3D Ctri 3 CASA Ctri 4 CAPS 5 Reri Tine Ct CARS 2D To enter the CARS 2D module If you have a molecule in 3D the program will try to figure a suitable 2D conformation of the molecules on the screen and will add alpha and beta bonds to preserve their stereochemistry See section 10 5 for details and limitations CARS 3D To enter the CARS 3D module If you have a molecule in 2D the molecule s 3D configuration will automatically be computed if possible see section 10 5 for details and limitations CASA To enter the CASA module from where you can perfo
145. will match it perfectly will be chosen You have to indicate the squeleton atoms of the target and not the functional groups Usually you will only ask for one or two critical carbon atoms because the likehood of perfect matching will be much less The program will indicate the critical atoms among the essential atoms by displaying their atom numbers in a different color during the search Note that this option doesn t make the search much faster but it would be very useful if the database of precursors is very large To cancel Critical Atoms indicate No Critical Additional Select More to find additional precursors that fit adequately except for a functional group that is very hard to modify chemically In the Just mode these groups are worth 9999 points each and the precursor will be rejected In More mode their score is set to 100 The More options finds a precursor that would have been overlooked otherwise With the With Transformation option in Place a problem message will appear around the trouble making atom or group This option is there to suggest alternate ideas and to modify the precursor accordingly Similar Select Remove to remove similar precursor and keeps only the best ones For example if two precursors are identical except for one functional group the program will only keep the one that has the easiest chemical transformation to make to get the right functional group on the target Remove the default option w
146. y 2 4 di C methyl D glucose Ref S Hanessian et al CJC 55 1111 1977 Dbase CHIRON File ACYCLIC 6 37 Score 78 Prec Mol MatchKind FunctP FunctM Ratio Score 1 1 Extremity COX COOX 90 2 2 Chain CHMe r CHMe T 20 100 3 3 Chain CHOX 1 CHOX l 17 100 4 4 CHMe CHMe 205 1005 5 5 CHOX 1 17 70 6 6 Extremity CH20OX CXX 19 50 Losses and bonuses 8 Precursor extremity matches asymmetric center 7 5 Too many chemical manipulations to 85 Miscellanous Bonus 9 102 save targets and parameters for batch job Precursor searches may be done in batch mode after the search parameters have been selected Once all parameters are specified select Batch instead of Find You will have to enter a name for this job The job is entered in a local queue You can put more than one job in this queue To start the search in background chiron b amp You will then see the list of jobs that are waiting After you indicate Batch you cannot remove the job from the queue in Chiron but you can do it by editing the filebatch dat file in your current working directory To retrieve the precursors found for each target use the Get command You can kill a job that is executing in batch by typing kill 4 where is the number of the job between square brackets which you should have noted when you type the command otherwise use the jobs command If you stop the job or if it was
147. y around the vertical axis that passes through the center of a molecule Every alpha and beta bond will be inverted keeping the molecule itself unchanged Me OH Figure 5 11 Restore returns the molecule to its original position before you entered the Rotate dialog To clear the work area You will be asked to confirm 5 59 CASA The CASA module will recognize the stereochemical features in your molecules from many different perspectives 6 1 Working examples for CASA After a molecule has been drawn on the screen or loaded from a file using CARS activate the CASA module by pointing to the CASA menu box Examine the commands in the menu and select the operation you want Point to the appropriate menu box and the information will appear on the screen Enter or draw a molecule of your choice ex Forskolin etc 1 Ask for R S observe then indicate Tree and click on any asymmetric carbon center Finally indicate two points the top and the bottom left extremities of the tree to place it You can now use the Scrap option to erase the R S descriptors and the Priority Tree from the screen Priority Tree FORSKOLIN R and S Weight Decreasing Figure 6 1 R S notation applies only to asymmetric atoms with four ligands ex C S Compounds with chiral axes planes etc are not considered In cases where the program cannot make an assignment for a non planar carbon equal priorities the program will display an
148. y the next non discarded precursor Press Last to see the last non discarded precursor Move the slider to see a specific precursor list number Press Discard Current to discard the current precursor from the list Press Discard Rest to discard the following precursors the current precursor will not be discarded Press Done to stop the scan and keep the precursor on the screen or Cancel to remove it When the target molecule is somewhat large the structure may be compressed on the screen Discarded precursors are logically discarded not physically You may undiscard a precursor by dragging the slider bar to the list number of the precursor you want to see When you save a precursor job the program will not save discarded precursors in the file and all remaining precursors will be numbered consecutively When you use the Report command only remaining precursors will be listed RSBC Rapid Scanning of Best Combinations To rapidly visualize the best combinations of precursors that were found on the screen After selecting RSBC the program will move and scale the target molecule in the middle of the screen and place the precursors if the combination is made of only two precursors If there are more than 2 precursors for a given combination the program will ask you for the location of each precursor You press the First button to display the first combination of precursors Press Previous to see the previous combination Press Next butt
149. y the stereochemistry of ring junctions use the Alpha or Beta commands 5 When the structure functional groups stereochemical features etc have been drawn select Update to clean up the drawing You are now ready to do the following e Save the structure User Molecule proceed with CASA or CAPS proceed with CARS 2D reaction schemes etc 6 Select the Grid command You can now draw structures by joining the intersection points of the Grid Expert Mode You will notice that some letters in the palette tools commands are underlined Typing those letters on the keyboard will activate the corresponding commands these shortcuts can be used to select commands without using the mouse There is also a shortcut for the Alpha and Beta commands 4 6 Adding to the precursor database You will surely want to increase the number of precursors in the main database You can create a new database then import your precursors by using the File Import CIF format menu item Your precursors should be in the Chiron Program Interchange Format see Appendix A To transfer your molecules to CIF format you can use the mdltochiron program which will convert a MDL SDfile to CIF If your molecules are in a different chemical file format you can use the Babel freeware program available on the Internet to convert them into MDL file format You can also write a program to transfer your files to the CIF or you can redraw your precursors with the program whi

The Chiron Program User's Manual

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