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1. r 0 E gt gt Dim Yim 0 0 1 0 m l1 where j 4 are normalized real spherical harmonic functions and Qj are the expansion coefficients The parameters 0 4 are the usual spherical coordinates with respect to the centre of the harmonic expansion CoH ParaSurf normally sets the CoH to be equal to the molecular center of gravity CoG Because the spherical harmonics functions form a complete orthonormal spherical basis set it can be shown that they transform amongst themselves under rotation according to 2 7 Vim 8 0 Rn BY in 0 9 where Ry m a By are real Wigner rotation matrix elements expressed in terms of the Euler z y z rotation angles 2 7 Using this rotational property it is straight forward to show that a rotated SH expansion may be constructed from an unrotated expansion by rotating the original expansion coefficients 3 l im gt R mm A BS Big m l In order to calculate a superposition between a pair of molecules ParaFit translates the CoH of the moving molecule B to that of the fixed reference molecule A and then searches for the rotation that minimizes the distance between the corresponding pairs of spherical harmonic expansions D euctpean fic 0 0 R a B y7 rs 0 dQ By exploiting the orthonormality of the basis functions this expression reduces to D gucupean la lol 2a b E CEPOS InSilico 2009 BACKGROUND 6 ParaFit2. PROGRAM USAGE 16 ParaFit 09 User Manual SDF files to be processed from a specific file with each file name in the list file being separated by space or newline characters For example the command parfait canonical read 74 lis canonicalises the orientations of 74 selected drug molecules listed in the file 74 1lis Figure 7 shows the resulting orientations This figure was produced with the help of two ParaShift Unix utility scripts sdf2pdb and pdb2one inorder to concatenate the SDF files into an single PDB file for display using Hex 10 Figure 7 Left 74 selected drug molecules in their L 6 canonical orientations right the same molecules rotated by 900 about the z axis Because no reference file is used in canonical mode the new output file names are generated with a default affix of canonical Hence the above example would create files of the form movingl_ canonical sdf moving2_canonical sdf etc The affix option may be used to explicitly specify how the output files should be named For example the command parfait canonical read 74 lis affix c produces movingl1_c sdf moving2_c sdf etc SE CEPOS InSilico 2009 We PROGRAM USAGE 17 ParaFit 09 User Manual 3 6 Move Mode In move mode no superpositions are calculated Instead each molecule is transformed according to a given sequence of rotation and translation operations For example the command parfait move ry 90 tx
3. Weg Wa S gt where Wsurrace represents a user defined weight factor etc In ParaFit all similarity score weight factors are normalized to unity before use However the Euclidean distance function may be selected if un normalised or explicitly scaled property combinations are required 2 2 Rotational Correlations ParaSurf superposes molecules using a brute force rotational search over the three Euler rotation angles Conceptually each moving molecule is rotated with respect to the fixed reference molecule and the Euler rotation that gives the greatest similarity or smallest distance score is recorded This is essentially a Fourier correlation search in Euler angle coordinates However because good SSeS CEPOS InSilico 2009 BACKGROUND 7 ParaFit 09 User Manual superpositions may be achieved using only low order harmonic expansions it is not necessary to use fast Fourier transform FFT techniques to accelerate the calculation Indeed in our experience the FFT is only of benefit when L gt 16 which is considerably higher than the recommended default ParaFit value of L 6 In addition to using low order correlation searches ParaFit s superposition calculations are accelerated in two further ways The first technique exploits the fact harmonic expansions to order L can have no more than L2 local maxima Hence ParaFit initially uses relatively large angular search steps of around 8 to cover the search
4. aT R Set the angular step size A for the first pass rotational search The default value is 8 Thi ti i Sen is option may be abbreviated as shown angle2 A Set the angular step size A for the second pass rotational refinement search The a2 A default is 2 This option may be abbreviated as shown read file Read a list of SDF input file names from the given file write file Specify the explicit name of a single SDF output file This is only permitted when there T CEPOS InSilico 2009 PROGRAM USAGE 20 Command Line Option ParaFit 09 User Manual Description is just one output file score file Write similarity scores to a given file the default file name is parafit pft noscore Suppress the scores file dif file In matrix mode write distance scores to a given difference format output file the default file name is parafit dif nodif Suppress the difference distance file log file Write all messages to a named log file the default log file is parafit 1log nolog Suppress the output of a log file stdout Write all messages to the Unix terminal or Microsoft Windows command console standard output nostdout Suppress writing messages to standard output this is the default sdf Write new SDF files after a superposition or canonicalization calculation This is the default nosdf Suppress the output of new SDF f
5. distance scores abcd dif Any text following a hash comment character is provided only to indicate the order in which the distance values appear in the file and is ignored by the clustering program a sdf b sdf c sdf d sdf Figure 5 The dendrogram created from abcd dif using the ParaShift dif2jpg utility If the main aim of a matrix mode calculation is to conduct a cluster analysis it is often worthwhile using the nosdf option to prevent ParaFit creating any SDF files This avoids filling the working directory with a large number of unwanted files and helps to speed up the calculation Depending on CPU speeds ParaFit can perform rotational superpositions from 2 to 10 times faster than the time E CEPOS InSilico 2009 PROGRAM USAGE 15 ParaFit 09 User Manual required to write a new SDF file Hence the speed up can be considerable when clustering large datasets 3 5 Canonical Mode In canonical mode ParaFit places each molecule in a standard or canonical orientation such that its maximal radial extent is aligned with the positive z axis and whilst keeping this axis fixed its maximal equatorial extent is aligned with the positive x axis For spherical harmonic expansions to order L 2 this corresponds to aligning molecules to the coordinate axes using their ellipsoidal radii or moments of inertia for example However such low order alignments are ambiguous with respect to 180 fl
6. 09 User Manual where b represents the vector of rotated SH expansion coefficients of the moving molecule etc We call this a Euclidean distance function due to its analogy to Euclidean distances in ordinary 3D space This function has units of A2 and clearly depends on the relative size of the molecules being compared However when comparing multiple molecules it is often convenient to use normalized distance or similarity functions in which identical molecules give a score of zero or unity respectively For example dividing by the sum of the magnitudes of the SH shape vectors gives the Hodgkin similarity score 2ab _ D puctmean jal p aP HODGKIN Similarly ParaFit implements the Carbo and Tanimoto similarity functions as a b Scarso alld 5 s _ ab TANIMOTO 2 R2 9 jal a2 It is generally not obvious which of the above scoring functions is to be preferred In our experience they all give good pairwise superpositions with L gt 6 SH expansions ParaFit uses the above Tanimoto function as its default similarity function For each of the above similarity functions ParaFit allows a composite score to be calculated for an arbitrary combination of the SH surface shape and the four key ParaSurf local surface properties 8 namely molecular electrostatic potential MEP ionization energy IEL electron affinity EAL and polarizibility a SURFACE S _ MEP IEL EA ay S WSURFACE WyppS HWS
7. 10 movingl sdf moving2 sdf rotates each molecule relative its CoH by 90 about the y axis and then translates the result by 10A in the x direction ParaFit uses the convention that a positive rotation angle defines an anticlockwise rotation of the molecule as seen when looking along the axis of rotation towards the origin All coordinate transformations rx ry rz tx ty tz are applied in the order in which they are appear on the command line It is also possible to specify that each molecule should have its CoH shifted to the global coordinate origin using the move coh option For example parfait move coh ry 90 tx 10 movingl sdf moving2 sdf rotates and co locates the CoH of each molecule 10A along the positive x axis For completeness ParaFit also allows coordinate operations to be applied relative to the CoG For example the command parfait move cog movingl sdf moving2 sdf moves all molecules such that their CoGs lie at the global coordinate origin Conversely specifying parfait movetcog ry 90 movingl sdf moving2 sdf rotates all molecules about their individual CoGs From the above descriptions the move option is seen to be an abbreviation for move coh i e move relative to CoH Like canonical mode move mode adds an automatic file name affix to all output files but in this case the default affix is parafit As before this may be changed by the affix option For example
8. CoG coordinates lt SPHERICAL HARMONIC SURFACE gt The ParaSurf SH surface shape coefficients lt SPHERICAL HARMONIC MEP gt The ParaSurf SH MEP expansion coefficients lt SPHERICAL HARMONIC EA gt The ParaSurf SH EA expansion coefficients lt SPHERICAL HARMONIC IEL gt The ParaSurf SH IEL expansion coefficients lt SPHERICAL HARMONIC ALPHA L gt The ParaSurf SH a expansion coefficients Laas CEPOS InSilico 2009 PROGRAM USAGE 9 ParaFit 09 User Manual 3 PROGRAM USAGE ParaFit is a command line driven program and is normally launched from a Unix terminal window or a Microsoft Windows command console The program accepts a number of optional parameters to control the type of calculation followed by the names of one or more SDF files The basic command syntax is parafit options lt sdf files gt where square brackets represent optional parameters and angled brackets represent required file names respectively The optional parameters generally have sensible defaults and may often be abbreviated The full list of ParaSurf command options is described in Section 3 7 By default ParaFit creates new SDF files based on the names of the supplied input files and it writes a record of each calculation to a log file parafit 1log ParaFit does not write to the terminal unless errors are encountered However these behaviours may be changed usin
9. Hence for example the commands cat a sdf b sdf gt ab sdf parafit fit ab sdf bcd sdf will produce two results files bcd_ab_1 sdf and bcd_ab 2 sdf which contain the three database molecules fitted to the first and second query molecules from ab sdf respectively 3 3 Scoring Functions and Property Options The Hodgkin Carbo or Tanimoto similarity scores or Euclidean distance scores may be selected using the options hodgkin carbo tanimoto or euclidean respectively Similarly the local property to use during the superposition may be specified using one of the options surface surface shape mep MEP iel IEL eal EAL or alpha aL Combinations of surface properties may be specified using the weights option For example parafit carbo weights surface 0 8 mep 0 2 lt SDFs gt gives a Carbo superposition based on 80 shape similarity combined with a 20 contribution from the MEP For the similarity scores ParaFit normalises the weight factors to unity before use Hence the above calculation could be specified equivalently as parafit carbo weights surface 80 mep 20 lt SDFs gt If un normalised scores are required the Euclidean scoring function should be specified parafit euclidean mep lt SDFs gt 3 4 Matrix Mode In matrix mode each molecule is treated in turn as a query molecule and all others are superposed onto it For example if N molecules are given as input then N mult
10. space In order to sample angular space evenly and efficiently these angular samples are generated from the vertices of an icosahedral tessellation of the sphere For a given angular step size this gives around 30 fewer sample points than a na ve equi angular grid 3 Once the approximate location of maximum similarity has been identified it is then refined using a localized grid search in steps of 2 Both angular step sizes may be adjusted by the user The second acceleration technique is used when comparing multiple molecules Rather than separately rotating each of the moving molecules in turn it is more efficient to rotate the SH expansions of only the reference molecule and to compare these against each of the moving molecules Thus relatively expensive SH rotations are applied to just one rather than N molecules Once the optimal rotations have been found the moving molecules are rotated using the inverse of the corresponding reference rotations Using these techniques a pair of molecules may be superposed in around 1 20s on a 1 8GHz Pentium Xeon processor and computation times may be further reduced by a factor of up to 5 if multiple molecules are compared in a single ParaFit run 2 3 Transformed SDF Files Once the rotational orientation has been determined ParaFit writes each of the moving molecules to a new SDF file Multi molecule SDF files are fully supported Each new file contains rotated and translated instances of the
11. PPORT 22 ParaFit 09 User Manual 4 SUPPORT Any questions regarding ParaFit should be sent to support ceposinsilico com SSE CEPOS InSilico 2009 REFERENCES 23 ParaFit 09 User Manual 5 REFERENCES 10 J H Lin T Clark An Analytical variable resolution complete description of static molecules and their intermolecular binding properties J Chem Inf Model 2005 45 1010 1016 M E Rose Elementary Theory of Angular Momentum 1957 Wiley New York D W Ritchie G J L Kemp Fast Computation Rotation and Comparison of Low Resolution Spherical Harmonic Molecular Surfaces J Comp Chem 1999 20 4 383 395 D W Ritchie G J L Kemp Protein Docking Using Spherical Polar Fourier Correlations Proteins Struct Funct Genet 2000 39 178 194 T Clark A Alex B Beck F Burkhardt J Chandrasekhar P Gedeck A H C Horn M Hutter B Martin G Rauhut W Sauer T Schindler and T Steinke VAMP 8 2 2002 available from Accelrys Inc San Diego USA J J P Stewart MOPAC2000 1999 Fujitsu Ltd Tokyo Japan MOPAC 6 0 was once available as J J P Stewart QCPE 455 Quantum Chemistry Program Exchange Bloomsville Indiana 1990 L C Biedenharn J C Louck Angular Momentum in Quantum Physics 1981 Addison Wesley Reading MA B Ehresmann M J deGroot A Alex and T Clark New Molecular Descriptors Based on Local Properties at the Molecular Surface and a Boiling Point Model Derived
12. SCIENCE FOR SCIENTISTS Impressum Copyright 2009 by CEPOS InSilico Ltd The Old Vicarage 132 Bedford Road Kempston BEDFORD MK42 8BQ www ceposinsilico com Manual David Ritchie Software David Ritchie Layout www eh bitartist de NIAS CEPOS o TABLE OF CONTENT TABLE OF CONTENTS 1 INTRODUCTION 2 BACKGROUND 2 1 Spherical Harmonic Superpositions 2 2 Rotational Correlations 2 3 Transformed SDF Files 3 PROGRAM USAGE 3 1 Fitting Mode 3 2 Multi Molecule SDF Files 3 3 Scoring Functions and Property Options 3 4 Matrix Mode 3 5 Canonical Mode 3 6 Move Mode 3 7 Summary of Input and Output Files 3 8 Summary of Command Line Options 4 SUPPORT 5 REFERENCES ParaFit 09 User Manual Noo Ol 10 12 13 13 15 17 17 18 22 23 Laas CEPOS InSilico 2009 We INTRODUCTION 4 ParaFit 09 User Manual 1 INTRODUCTION ParaFit superposes and compares molecules using the spherical harmonic SH expansions of the molecular surface and local surface properties calculated by ParaSurf 1 By exploiting the special rotational properties of the spherical harmonic basis functions 2 computation times can be reduced by several orders of magnitude compared to conventional shape matching algorithms 3 4 Hence the ParaFit module is an essential component of the ParaSurf suite for virtual high throughput screening studies where very large numbers of compounds need to be assessed ParaFit provides t
13. alculation creates a similarity score file of this name Any existing score file is overwritten The score file may be named explicitly using the score option The score file is suppressed by noscore parafit pft Each ParaFit matrix mode run creates a difference distance file of this name parafit dif Any existing difference file is overwritten The file may be named explicitly using the dif option The difference file is suppressed by nodif Each ParaFit matrix mode run writes the calculated similarity or distance matrix to a comma seperated values or csv file of this name Any existing csv file is over written The file may be named explicitly using the csv option The csv file is suppressed by nocsv parafit csv 3 8 Summary of Command Line Options Table 4 describes the ParaFit command line option keywords A shorter version of these descriptions may be produced directly from the program using the help option Table 4 List of ParaFit command line options Command Line Option Description fit Superpose one or more SDF files to a given reference SDF file This is the default f mode of calculation The first SDF file is treated as the fixed reference molecule All subsequent SDF files are treated as moving molecules to be fitted to the reference structure At least two SDF files must be given in this mode This option may be abbreviated as shown matrix Supe
14. f surface 1 0 had been specified This keyword may be abbreviated as shown noweights Do not superpose multiple SH properties with user supplied weights Instead now molecules will be superposed using a single property with surface shape surface as the default property The default behavior is to superpose using a single property i e as if noweights had been specified This keyword may be abbreviated as shown surface Superpose molecules using SH molecular surfaces this is the default superposition surface W property If the weights option has been specified a numerical weight factor W must be provided after this option keyword If the noweights option has been specified no weight factor should be given mep Superpose molecules using the SH molecular electrostatic potential MEP or include mep W the MEP with the given weight factor W in a multi property score as described above iel Superpose molecules using the SH local ionization energy IEL or include the IEL with iel W the given weight factor W in a multi property score as described above eal Superpose molecules using the SH local electron affinity EAL or include the EAL with eal W the given weight factor W in a multi property score as described above alpha Superpose molecules using the SH polarizability a1 or include the polarizability with alpha W the given weight in a multi property score as described above angle A f
15. from Them 2004 J Chem Inf Comp Sci 44 658 668 http www let rug nl kleiweg clustering http www csd abdn ac uk hex SSE CEPOS InSilico 2009
16. g one of the above move options Tas Apply an anticlockwise rotation of Y degrees about the y axis to the current orientation of each molecule in the given list of SDFs The initial coordinate origin is selected using one of the above move options T CEPOS InSilico 2009 We PROGRAM USAGE 21 Command Line Option ParaFit 09 User Manual Description rZ Z Apply an anticlockwise rotation of Z degrees about the z axis to the current orientation of each molecule in the given list of SDFs The initial coordinate origin is selected using one of the above move options tx X Apply a translation of X Angstroms along the x axis to the current orientation of each molecule in the given list of SDFs The initial coordinate origin is selected using one of the above move options ty Y Apply a translation of Y Angstroms along the y axis to the current orientation of each molecule in the given list of SDFs The initial coordinate origin is selected using one of the above move options SEZIZ Apply a translation of Z Angstroms along the z axis to the current orientation of each molecule in the given list of SDFs The initial coordinate origin is selected using one of the above move options debug Produce verbose debugging output Po Print the program version number This option may be abbreviated as shown help Print a summary of all ParaFit program options l CEPOS InSilico 2009 SU
17. g Unix style option keywords For example parafit nolog stdout lt sdf files gt suppresses the log file and directs all output messages to the standard output Unix terminal or Windows console Similarly the nostdout option suppresses all standard output The main ParaFit operating modes are described in the following sections These sections use some example SDF files which contain SH data blocks calculated by ParaSurf for four dopamine antagonists Although ParaSurf SDF files typically follow certain naming conventions the highly abbreviated file names listed in Table 2 are used here for clarity ParaFit automatically handles any files that use the GZIP gz or BZIP2 bz2 file compression formats There is essentially no limit on the number or size of SDF files or the number of molecules in a multi molecule SDF file that can be processed Multiple multi molecule SDF files may be processed in a single ParaFit run Table 2 The four dopamine receptor antagonist examples used in this Manual Name WDI Number SDF File Lorazapam WDI 0030 a sdf Diazepam WDI 0032 b sdf Temazepam WDI 1451 c sdf Olanzapine WDI 1416 d sdf T CEPOS InSilico 2009 PROGRAM USAGE 10 ParaFit 09 User Manual 3 1 Fitting Mode In fitting mode the first supplied SDF file is treated as the query or fixed molecule and all subsequent molecules are treated as moving or database molecules whic
18. h are to be fitted to the fixed query Hence at least two SDF files must be given in this mode parafit query sdf dbl sdf db2 sdf Each database molecule is first translated to the CoH of the query structure and its CoH and CoG are updated accordingly The best superposition is then found using the two stage brute force Fourier rotational search as described above In order to indicate that the new files represent the original molecules transformed into the frame of the query the ParaFit output files are named as db1_query sdf db2_query sdf etc If a calculation produces only one SDF output file it may be named explicitly using the write option However the above file name generating rule must be used when processing multiple files Figure 1 shows the contents of the log file after superposing diazepam b sdf onto lorezapam a sdf using the default calculation parafit a sdf b sdf Figure 2 shows the corresponding molecular superposition in which the new SDF file b_a sdf contains a rotated diazepam molecule translated into the lorazepam coordinate frame Copyright c 2006 09 Dave Ritchie University of Aberdeen Marketed under licence by CEPOS InSilico Ltd hnome staff dritchie parafit parafit 8 05 bin parafit i586 fit a sdf b sdf Fitting superpose database molecules to query file Spherical hamonic order 6 Similarity score function Tanimoto Angular search step 8 00 gt 500x45 22500 samples Angular refineme
19. hree main calculation modes In the default fitting mode ParaFit superposes one or more moving molecules onto a single fixed reference molecule The program can also perform all versus all superpositions in which each molecule is superposed in turn onto all others In this matrix mode a table of distance scores is written out in a format suitable for subsequent clustering analysis for example In addition to superposing molecules ParaFit may also be used to align molecules to the coordinate axes in order to place then in a standard or canonical orientation This is often a useful first step in QSAR studies ParaFit can also apply arbitrary coordinate transformations to a given list of ParaSurf VAMP 5 or Mopac 6 SDF files These transformations could be supplied as part of a processing pipeline by other superposition programs e g ParaMatch that do not have the capability to rotate complex quantum mechanical QM properties such as quadrupole and octupole moments and atomic orbital charge density matrix elements ParaFit s ability to rotate all of the orientation dependent QM information in an SDF file eliminates the need to recalculate expensive QM quantities for new molecular orientations SSE CEPOS InSilico 2009 BACKGROUND 5 ParaFit 09 User Manual 2 BACKGROUND 2 1 Spherical Harmonic Superpositions SH molecular surface shapes are represented as radial expansions of the form
20. i molecule SDF files are produced as output with each file containing the original query molecule plus the remaining N 1 molecules T CEPOS InSilico 2009 We PROGRAM USAGE 14 ParaFit 09 User Manual superposed onto it Thus each output file correspond to one row of the NxN matrix Hence for example the command cat a sdf b sdf c sdf d sdf gt abcd sdf parafit matrix abcd sdf produces four output files named abcd_matrix_1 sdf abcd _ matrix 2 sdf etc each of which will contain four molecules sorted by similarity with the query molecule If desired sorting can be suppressed by using the nosort option In matrix mode ParaFit writes an additional file of similarity scores in the difference table format of Kleiweg s publicly available clustering program 9 For example parafit matrix hodgkin dif abcd dif abcd sdf generates a file of triangular distance scores using D 1 S if necessary as shown in Figure 4 Figure 5 shows the dendrogram created from this file using the ParaShift utility script dif2jpg This dendrogram readily confirms that olanzapine d sd is the outlier of the group The option nodif suppresses the difference file sdf 1 LORAZEPAM sdf 1 DIAZEPAM sdf 1 TEMAZEPAM sdf 1 OLANZAPINE 01624636 02260344 01412539 03403905 03975538 02909502 4 a b c d 0 0 0 0 0 0 Figure 4 Example ParaFit output file of difference
21. iles affix F When generating new SDF files in canonical or move mode construct output file names by inserting the given affix F between the root and extension components of the input SDF file names In canonical mode the default affix is canonical In move mode the default affix is parafit move coh Move one or more SDF files to locate their harmonic expansion centers CoHs at the origin and apply any subsequent transformations rx tx etc relative to this new origin in the order in which they appear on the command line move cog Move one or more SDF files to locate their centers of gravity CoGs at the origin and apply any subsequent command line transformations rx tx etc relative to this new origin in the order in which they appear on the command line move coh Apply a given sequence of transformations rx tx etc in the order in which they move appear on the command line to each molecule relative to the individual molecular CoHs This option may be abbreviated as shown move cog Apply a given sequence of transformations rx tx etc in the order in which they appear on the command line to each molecule relative to the individual molecular CoGs This option may be abbreviated as shown SYXEX Apply an anticlockwise rotation of X degrees about the x axis to the current orientation of each molecule in the given list of SDFs The initial coordinate origin is selected usin
22. ips about the coordinate axes Therefore by default ParaFit calculates canonical alignments using SH expansions to L 6 in order to eliminate any ambiguity in the final orientation except for the rare cases of molecules with intrinsic Coy symmetry The syntax for canonical alignments is parfait canonical movingl sdf moving2 sdf As before the SH surface shape function is used by default although any local surface property may be used In canonical mode molecules are always aligned by maximizing the un normalised SH property values with respect to the axes regardless of any command line scoring or weighting options The values subsequently written to the scores file are the magnitudes of the corresponding SH property vectors calculated at the current SH expansion order Hence by default the scores file orders canonicalised molecules by surface area Figure 6 shows the four example dopamine antagonists in their L 6 canonical orientations Figure 6 Left the L 6 SH surface shape canonical orientations of lorazepam diazepam temazepam and olanzapine right the same molecules rotated by 900 about the z axis Most operating systems limit the number of characters allowed in a command line and this implicitly limits the maximum number of SDF files that may be specified using the command line syntax In order to circumvent this limit the read option may be used to direct ParaFit to read the list of SE CEPOS InSilico 2009
23. n performed as cat b sdf c sdf d sdf gt bcd sdf parafit fit a sdf bcd sdf In other words a sdf is treated as the query structure which will be compared against the database of molecules in bcd sdf The result will be a new multi structure SDF file called bed_a sdf which will contain each of the database molecules rotated into superposition with the query These will be ordered by similarity with the query structure with the most similar molecules appearing first If desired the original order may be maintained using the nosort option When performing similarity searches against a large database it is often desirable to retain only the most similar structures or hits In ParaFit this may be achieved using the hits option For example parafit fit hits 20 query sdf database sdf ES CEPOS InSilico 2009 PROGRAM USAGE 13 ParaFit 09 User Manual will return the 20 molecules at most in a file called database _query sdf which most closely match the given query molecule If desired multiple database files may be searched in a single run For example the command parafit fit hits 20 query sdf dbl sdf db2 sdf will produce two output files db1_query sdf and db2_query sdf which together contain the 20 molecules at most that most closely match the given query molecule If the first SDF file contains multiple molecules then each of these molecules is treated as the query molecule in turn
24. nt step 2 00 gt 8x8 8 72 samples Property weights SURFACE 1 00 MEP 0 00 IEL Detected 1010 MB main memory Reading a sdf a sdf 1 LORAZEPAM Reading b sdf b sdf 1 DIAZEPAM Input data read in 0 025 seconds Estimating 318 Kb of input text data 159 Kb molecule Scoring Query a sdf 1 LORAZEPAM 0 98375364 b sdf 1 DIAZEPAM Scored 1x1 in 0 064 seconds 15 57 sec Figure 1 An example ParaFit log file parafit log CEPOS InSilico 2009 PROGRAM USAGE 11 ParaFit 09 User Manual Writing score summary file parafit pft Query a sdf 1 LORAZEPAM Collecting 1 molecules from b sdf Collecting b sdf 1 DIAZEPAM Writing b_a sdf Output files written in 0 043 seconds Parafit done in a total of 0 13 sec Maximum memory allocation 343 Kb Parafit 08 05 log stopping at Sat Jun 14 17 21 40 2009 on host wigner Figure 1 continued Figure 2 The superposition of lorazepam and diazepam shown using the calculated diazepam orientation b_a sdf in the coordinate frame of lorazepam a sdf The above example uses default values for the spherical harmonic expansion order L 6 local surface property surface shape and similarity score function Tanimoto The same calculation could be specified more explicitly as parafit fit surface tanimoto order 6 al 8 a2 2 lt sdf s gt where a1 and a2 refer to the low and high resolution search increments respectivel
25. original atom coordinates point charges molecular and atomic multipoles charge density matrix elements and spherical harmonic expansion coefficients ParaFit treats files with an extension of asd as ParaSurf ASD files i e anonymous SDFs The main ParaSurf data blocks that are transformed by ParaFit are listed in Table 1 All other quantities in the new SDF file are copied without change from the original data Table 1 The main data blocks that ParaFit transforms after a superposition calculation SDF Data Block Version SENE AGN COONAN EDIE The atom coordinate and bond tables in MDL format lt VAMPBASICS gt The VAMP molecular heat of formation HOMO and LUMO energies and dipole moments lt MOPACBASICS gt The MOPAC molecular heat of formation HOMO and LUMO energies and dipole moments lt NAO PC gt The natural atomic orbital point charges calculated by VAMP lt DIPOL gt The molecular dipole moment calculated by VAMP or Mopac See CEPOS InSilico 2009 BACKGROUND 8 ParaFit 09 User Manual lt QUADPOL gt The molecular quadrupole moment calculated by VAMP or Mopac lt OCTUPOL gt The molecular octupole moment calculated by VAMP or Mopac lt ATOMIC MULTIPOLES gt The VAMP Mopac atomic MEP multipoles lt DENSITY MATRIX ELEMENTS gt The VAMP Mopac atomic orbital density matrix elements lt MOLECULAR_CENTERS gt The ParaSurf CoH and
26. parfait affix 0 move coh movingl sdf moving2 sdf produces movingl 0 sdf moving2_0 sdf etc 3 7 Summary of Input and Output Files ParaFit assumes all input data files are SDF format files There is no requirement that SDF data files are named with the sdf extension However anonymous SDF files ASD files must have an extension of asd in order to be processed properly ParaFit constructs SDF output file names from the given input file names Hence if an input file name uses upper case then so too will the corresponding output file If an input file does not have an extension then neither will the output file However if ParaFit fails to open a file with no extension it will append sdf to the name and try again Any file names that end with gz or bz2 are presumed to be compressed files compressed l CEPOS InSilico 2009 PROGRAM USAGE 18 ParaFit 09 User Manual input files will cause compressed output files to be generated In addition to the above rules ParaFit writes up to three files of additional information as described in Table 3 Table 3 Summary of ParaFit additional information output files File Name Description Each ParaFit run creates a log file Any existing file of the same name is parafit log overwritten The log file may be named explicitly using the log option The log file may be suppressed using the nolog option Each ParaFit fit matrix or canonical mode c
27. rpose two or more molecules in an all versus all manner to produce a matrix of m superpositions Each output SDF file name is constructed from corresponding pairs of moving and fixed reference file names At least two SDF files must be given in this mode This option may be abbreviated as shown canonical Align one or more molecules with the coordinate axes Each output SDF file name is constructed by appending the source file name with the default affix of canonical At least one SDF file must be given in this mode This option may be abbreviated as T CEPOS InSilico 2009 PROGRAM USAGE 19 Command Line ParaFit 09 User Manual D TOF ORN escription shown order L Set the spherical harmonic expansion order to use for superposition and a it canonicalization calculations The default value is 6 This option may be abbreviated to 1 ell hodgkin Perform superpositions by maximizing the Hodgkin similarity score This is the default score function carbo Perform superpositions by maximizing the Carbo similarity score tanimoto Perform superpositions by maximizing the Tanimoto similarity score euclidean Perform superpositions by minimizing the Euclidean distance score weights Superpose molecules using multiple local surface properties using a given numerical W weight factor for each property If no property keywords are given the calculation is performed as i
28. y In addition to the log file ParaFit writes a compact summary of each run to a scores file with a default file name of parafit pft This file lists the similarity scores and names of the original La CEPOS InSilico 2009 We PROGRAM USAGE 12 ParaFit 09 User Manual query and database files For example superposing the remaining three dopamine antagonists onto lorezepam and explicitly naming the scores file using the score option parafit a sdf b sdf c sdf d sdf score abcd pft gives the scores file shown in Figure 3 The scores are always ordered by magnitude Hence in this example diazepam b sdf is calculated to have the greatest surface shape similarity to lorazepam If desired the noscore option may be specified to suppress the scores file I 3 Query a sdf 1 LORAZEPAM 0 98375364 b sdf 1 DIAZEPAM 0 97739656 c sdf 1 TEMAZEPAM 0 96596095 d sdf 1 OLANZAPINE Figure 3 The contents of the example ParaFit scores file abcd pft showing the calculated Tanimoto similarity scores for the three database molecules with respect to the given query molecule 3 2 Multi Molecule SDF Files When dealing with more than just a handful of molecules it is often convenient to collect multiple molecules in a single multi molecule SDF file In ParaFit all calculations are applied to each molecule in each SDF file For example the above calculation could equally have bee
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