Forecaster – GUI User Guide 1.0
Contents
1. 20 20 Number of hydrogen bond acceptor s o 1000 Number of hydrogen bond donor s D 500 Total number of atoms 0 1000 Number of heteroatom s 0 1000 Number of oxygen atom s D 1000 Number of nitrogen atom s 0 1000 Number of sulphur atom s 0 1000 Number of metal atom s 0 o Rings D 1000 Number of rotable bond s i 6000 Ionizable group s i 200 logP 0 5 Polar Surface Area 0 500 logS Solubility D 500 Functional group None Filter Optional Minimum Maximum Acyl chloride a 0 0 Aldehyde 0 0 Alkyl chloride a 0 0 Alkyl bromide 0 0 Alkyl iodide a o 0 Amide a 0 0 COMBINATORIAL LIBRARY FROM 2D STRUCTURES This action is based on our program REACT 2 0 that takes two libraries of chemicals in 2D and a reaction scheme either from three separate mol files or a MDL rxn scheme file to prepare a combinatorial library In this new action the reaction is not defined using the 31 reactions manager The reaction scheme is given to the interface from the dialog box along with the two libraries of chemicals To define the reaction the reactant 1 reactant 2 and the product files in MDL mol format are required Combinatorial libraries from 2D schemes General reaction Scheme Reactant 1 File amineR1 mol Reactant 2 File acidR2 mol Product File product mol Diagram Board Libraries Upload Molecular Files Library of reactants 1 amines sdf Library of reactants2. 2 Chain s Protein File 3 Chain s Output Identify ligand residues in pdb Number of ligand residues 2 Proteins 1E2K pdb All 1KIM pdb All 1K12 pdb fiw All 1KI2 pdb wm 3 el Residue Name Chain Name Residue Number Residue 1 TMC Residue 2 THM Residue 3 PE2 500 SUPERPOSE PROTEIN STRUCTURES This action takes multiple protein structures pdb files and performs a sequence alignment in order to superpose all the proteins together Corresponding pdb files are then obtained This action is used in the Cross docking workflow 2 Superpose protein structures Standard Mode Number of protein s Protein File 1 Chain s Protein File 2 Chain s Output Superposition all pairs Number of ligand residues 2 Proteins 1 2K pdb All 1KIM pdb All superpose_output No x 2 Residue Name Chain Name Residue Number Residue 1 TMC Residue 2 THM A 500 A 1 EE PREPARE PROTEIN PDB TO MOL2 This action takes a protein pdb file add hydrogens to the protein according to the residue pKa and to water oxygen atoms searches for the optimal rotamers for asparagines glutamines and histidines reconstructs and optimizes missing side chains extract the ligand and finally outputs a protein file and a ligand file in mol2 format This format is appropriate for mos
3. chemicals The database format is a normal sdf file without any preparation This action is still in development and not yet fully validated 9 Substructure search Standard Mode Input Library File Library sd pj Substructure File motif mol Output File Name Results different from input file Name emer se SMALL MOLECULES SETUP LIGAND S FOR DOCKING In the publications describing FITTED 1 3 we referred to SMART as a program to setup the ligand files This action has been built from this program The ligand must have hydrogen atoms added when given to this action the user may use Convert 2D to 3D to add hydrogens or obtain this ligand from the Prepare protein pdb to mol2 action 3D structure files in sdf and mol2 formats are accepted and automatically detected by the action Setup ligand s for docking SIMPLE MODE F Input File 1e2k_lig mol2 w f Output File Name lig MMFF e Electronegativity equalization method Keep input file charges Atomic partial charges assignment us SHOW Dera Pa ADD HYDROGEN TO 2D STRUCTURES This action adds hydrogens to 2D molecules It is used by different actions when 3D is not ADVANCED MODE required but hydrogens need to be present CONVERT 2D TO 3D 35 This action takes the input structure s adds missing hydrogens converts from 2D to 3D and optimizes through energy minimization The file formats compatible
4. metabolism of xenobiotics by P450s Journal of Chemical Information and Modeling 2012 52 9 2471 2483 THE REGULAR USER INTERFACE GENERAL COMMENTS PROPER USAGE When using the platform it is important to avoid any white space in filenames The platform might recognize the file but the programs will fail to read the correct filename Use ll n dl dl or instead MINIMUM REQUIREMENTS FOR CLIENTS FORECASTER has been tested on Internet Explorer 7 and higher Firefox 3 6 and higher Chrome and Safari 4 and higher Other browsers including Internet Explorer 6 are not fully compatible with the interface FORECASTER However they can still be used but some logos fonts and other visual details may be affected LOGIN INTERFACE When loaded in a browser FORECASTER will display the login interface User inputs login name and password to log into the system The default account is admin with password fitted LOGIN LOGIN PASSWORD without the quotes HOME INTERFACE When logged in the user will see the home page This page presents the main features of the application MOLECULAR Guest User D Discovering Molecules Home Contact Us FAQ LOGOUT HOME WORKFLOWS MANAGER JOBS MANAGER FILE MANAGER SKETCHER REACTIONS SETTINGS Forecaster Drug Discovery Suite Dock ligand s using FITTED Y Setup protein for docking Y Filter by descriptors Docks ligand s using the automated Prepares the prot
5. platform s server users can use the system install by checking off yes next to Use system install and providing a path to the file If the plugin s executable file is not located on the platform s server users have to provide it and upload it to the platform Some programs work by reading the parameters from a keyword file usually a text file while others uses various arguments in command line To instruct the platform to either write a command line or a keyword file users choose whether or not the arguments for the executable file are located in a keyword file Selecting yes means that arguments are written inside of the keyword file Selecting no means that arguments are specified directly on the command line ADDING PARAMETERS Users add plugin parameters by clicking on Y Add a new parameter and filling out the appropriate fields Each parameter represents a field in the job manager edit screen Add a new parameter Order Label Name Field type Default Mode Value Keyword Mandatory 1 Inputformat Input_Forrnat select male simple Mode mole mol sdf pdb i Yes gt O ne El e The inputtile Input_File File gt simple Mode es gt 3 Output formi Output Forme Select gt sat simple Mode mole mol sdf pdb o es gt o E d The genera Output_File String Simple Mode YES Cancel Save Order specify the order in which fields appear on a form Label describe
6. reused in other jobs It is used as a transfer folder between a given user s jobs Mr FILES F Y Personal folder 33 Files User Files upload files to My Files folder File manager help SELECT All ZIP Selected COMBINE mol Delete Selected COPY to My Files Sort by Name y Filter by None EA Files per page All y Page Ka MY FILES 2xdw_lig mol2 molecule mol dle 6 2 kb dle 1 2 kb 2 e as w 2 e as FOLDER MY PROTEINS 14 Each user has a personal folder called My Proteins in which proteins files prepared for docking from different jobs can be saved to be reused in other docking jobs It is used inside the Docking with previously prepared protein files workflow MY_PROTEINS b 5 Files User Files upload files to My Files folder File manager help SELECT All ZIP Selected COMBINE mol Delete Selected COPY to My Files UNSELECT All ZIP Folder COMBINE mol2 Delete Current Folder Sort by Size Filter by None Files per page All Page 1f MY_PROTEINS 1E2K_pro_BindSite mol2 1E2K_pro_dock mol2 1E2K_pro_IS mol2 dle 6 1 kb dle 184 0 kb dle 3 5 kb 8 8 8 1E2K_pro_score mol2 1E2K_pro_site txt dle 3 2 mb 643 bytes E 2 E 4 JOB SPECIFIC FOLDERS Files used by each job are saved in the job s folder using a naming convention such as WF id number e g WF 8 The job specific folder will then read Not synchronized with
7. the system and it is at user s discretion to delete files contained in that folder MY FILES Self Docking WF 8 Y Personal folder MS Self Docking 2 Files Sep 08 2011 15 55 45 2 Files FILES AND ACTIONS Files are viewed with different programs depending on their type All text files are opened in a text editor directly integrated into the interface while mol2 and pdb files are visualized using the Open Astex Viewer java applet Files that are bigger than one megabyte 1 Mb must be downloaded in order to be viewed or edited Files located in all folders other than My Files folder can be copied to My Files by clicking on the Copy to My Files icon 15 SELECT All _ ZIP Selected COMBINE mol Delete Selected COPY to My Files UNSELECT All ZIP Folder COMBINE mol2 Delete Current Folder SKETCHER The sketcher is a tool that allows users to draw molecules using the SketchEl java applet Sketch your molecules 8 Sketcher help File Name Save Merge With File library sdf My Files testimol Load Mol Name P Merge O Block Select Transform Zoom Show Hydrogen Stereo Help Q SINIA 2 mA gt e Zo ADO O e SAVING AND LOADING FILES Users can save all molecules they draw using the sketcher in their My Files folder The platform provides an action called Convert 2D to 3D which converts the two dimensional drawings mol or sdf file format int
8. wf 1 Job ready to run Edit parameters Start Job Delete Job ADDING A NEW JOB Users add new jobs by clicking on Add a new job icon entering the job name choosing the workflow to be used and clicking continue HOME WORKFLOWS MANAGER JOBS MANAGER FILE MANAGER SKETCHER REACTIONS SETTINGS Add Job Name 2 Workflow Please Select e e Description memamo iii EDITING THE PARAMETERS AND SELECTING THE FILES TO PROCESS The editing screen displays the diagram created previously in the workflow manager In this section the user has to setup each action of the workflow This setup is done using a form which allows users to modify settings and select files to be processed in the job Editing Jobs Parameters Current job input files He Name Self Docking No fe chosen Workflow Self Docking COPY from My Files Description SS Diagram Board Upload Molecular Files Pdb te mol2 C 7 A Setup ligand s Setup protein Docking with FITTED C 7 A 10 First users have to upload files to be processed by directly uploading them to the system or by copying them from My Files folder There are two possibilities to add files to the job Files can be uploaded or transferred from My Files folder using the right hand side bar Current job input files x 2 1E2K pdb Choose File No file chosen COPY from My Files Upload Files Alternatively clicking on the container label
9. 2 acids sdf Output file Amides Combichem in 2D Gc O Output level default m pa SEARCH FOR ANALOGUES This action takes a library and a hit molecule and creates a new library of molecules from the library that are similar to the hit It uses the program SELEcT It can take either 2D or 3D structure files as input EXTRACT REPRESENTATIVE LIBRARY This action takes a library either 2D or 3D clusters the molecules by similarity and outputs a smaller library It uses the program SELEcT The clustering allows the user to remove similar molecules e g to keep the same diversity while reducing the number of molecules The number of clusters is the maximum number of molecules extracted based on the value of the Tanimoto coefficient used 32 Add descriptors Filter by descriptors Extract representative Prepare protein pdb library to mol2 Setup ligand s for Setup protein for docking docking l Dock ligand s using FITTED Extract representative library Standard Mode Input Library File library mol2 Output File Name library extracted different from input file Name Minimum Tanimoto 80 Coefficient 0 100 Standard MOL2 Format of input file 3D SD or 3D SDF FORECASTER SHOW a ae Advanced Mode COMBINATORIAL LIBRARY FROM 3D STRUCTURES This action is based on our program REACT 1 0 that takes two libraries of chemicals in 3D only and a r
10. 7 Ba AAEE a e e e EEE oo A E 17 Administrator INTEMaACe Setenil a add 19 USA scalac E T e dae vemos ue scae omer ras taneoaeiese 19 Userroles ana access aa 19 Adding PEWUSE SS 19 PIC AS Manal e O AT 20 Adding NEW pPIUCIN Ssss iann a N tui copes 20 Adding parameter ti 22 Adding new plugins TOM XML id 23 Contigurations Manage iii 24 OT UIE setU GS cies cuenta ceed eels ee cies cb 24 Save Database to PIU Sisa 24 ACOS nera io rodea 25 Se CUI DaS e esena oca 25 Dock ligands usine Elec nantes nia 25 PREGICE SOM USING WV CES rtorras 26 PROLCINS NUCICIC AGIOS scascccacce lax as icecncntsseiceocav ose idos 27 Mak proteins SIMI AA aa 27 SUD CFO OSE Protein Structure Sas 28 Prepare protein PAD TOMO siii E 28 Setup protein TOF GOCKING os 30 Mc A OI 30 do oo gio LO S A o E o A A tei iate Recut ta 30 Fiter NO SC de 31 Combinatorial Library rom 2D structures ido 31 SETTER TO ANO UE add 32 EXtractrepresentative raid 32 Combinatorial Library froni D StrUCtUrES asierea e a EE T eSeeeesents 33 Ada fragments to moleculas E E E 34 Pharmacophore identification and SearcCh occcooccnnononononanononanonnonarononaronnnnanononaronenanons 34 SUBS trUCTULS SECO ser 35 Small MMIOIG CUES airada 35 Setup gana s TOMOOCKIN Ges ini ios 35 Add Hydrogen to 2D structures cas 35 Convert 2d TOS ii 35 Clean Structure geomet A a ieee 36 Setup reactants for combichem in 3D occooccnncnncnncnncnnnonanononacononnncnnonorononanonnonacononacononan
11. IMOLE CUE AR ECASTER dw IN TE GRA TED PLA TF ORM F OR iTi com e 2 dd e EN Filter by descriptors i Con vert 2D to 3D Prepare protein pdb to mol2 Extract representa tive library h Create combinatorial library j Search for analogues Easy integration of 3rd party programs A AN IMAG y _ www molecularforecaster Molecular Forecaster Inc FORECASTER Platform 1 2 User Guide 13 June 2014 TABLE OF CONTENTS WEE OCMC COM criar oia 5 The RestlarUserinterace msi 6 General Comments Proper USA oocccononcononcnnonenonacnonannonarconanononacnonarnonarcnnaronocrononiacionarinna 6 Minimum requirements for ClientS ooccccoccncnncnnnncnnonannnnannnnarnnnncnnnnccnonannnnarnonarnnnnncnnnonos 6 A An e O AA 6 FO SMI y de eE a EE EE o 6 WO WIEN PONE C ASU CD rra 7 MESS tania 7 WorkHow None OT asienta 7 Adding anew WON IO WG aria 8 Building a WOM KTLOW diagr alti arrested 8 JODS M INEO secas 9 PCOS GT OW OD cis 9 Editing the parameters and selecting the files to process oooccccocnncnnnnnoncnnonaninnannnnnss 10 Executing and VIEwWiInNg JODS mico sc cenarancteauassscnaceiwdeaet EEEE TE REEE 13 o E ER 13 AA A OE A 14 E e e OO OO E E 14 Folder My Ao y e O OO OOO a ASE E 14 J OD SIOCITIC ONGC S iracec tata tetedeinncat bccatetuntscagtapadadstagun a A 15 FUSS ein oy IA o a e 15 A o o e A e reo E EE 16 Saving and Loading files enanrenal 16 Reactions Manap el usada 1
12. ING FITTED The action Dock ligand s using Fitted takes a ligand or a library of ligands and docks it to a protein It requires that the ligand s are setup properly using the action Setup ligand s for docking and that the protein has been prepared as well using the actions Prepare protein pdb to mol2 and Setup protein for docking as shown below The format of the input files is therefore taken care of by the platform 25 Upload Molecular Files Upload Molecular Files Prepare protein pdb to mol2 GC 7 A Setup ligand s for Setup protein for docking docking GC A GC 7 A Dock ligand s using FITTED GC 7 A When setting this action in Job manager a few boxes have to be filled The number of proteins to be used in the flexible mode is defined in the first box The protein file name is guessed by the interface as Setup protein for docking should be used in a preceding box Setup protein for docking Standard Mode f Number of protein s 1 Protein structure docking to rigid protein Protein File 1 1e2k_pro mol2 Number of Ligand s 1 Ligand Ligand File 1 te2k lig mol2 y Ligand Cutoff Output File Name process different from input file Name Prepare for Docking to flexible protein SHOW ee PREDICT SOM USING IMPACTS This action uses the IMPACTS program and predicts the most likely site s of metabolism SoM and transition state TS structures of small
13. R FILE MANAGER SKETCHER SETTINGS Editing Reaction Reaction Name Amide from carboxylic acid and ar Add a new rule Rule Rule Name Center Kept Atoms Removed Atoms New Atoms Rule2 amine n3 c3 hn hn Remove Rule1 carboxylic_acid_al c c3 0 o Remove Rule1 carboxylic_acid_ar c c2 0 o Remove Rule1 carboxylic_acid_vi c ca o O Remove Rule2 ammonium n4 c3 hn hn hn Remove Rule1 ester Cc c3 0 os Remove ADD RULES FROM THE REACTION BELOW 17 Alternatively users can draw and save each reactant and their product using the sketcher click on Save all to save the drawn structures and have the rules generated automatically by clicking on ADO RULES FROM THE Reaction BELOW File Edit View Help zy ly DIOIO NI DIOOO0O0O6OID gt 0 DIOOO0OO0O0OIi gt o 4 I gt File Edit View Help m le D O O X q Draw Product 1 File Edit View Help S E A 7 i O o ell i 0 9 xy NZ O10 gt O A O 4 Il b In the current version the use of the java applet has limitations Most of the coupling reactions the most widely used reactions when building libraries should work However rules for transesterification replacement of an alkoxide group by another alkoxide group are not figured out by the algorithm currently implemented Similarly reactions including two reacting atoms such as double bond reduction and metals G
14. ar and restart the diagram Undo a E t y 1 y A workflow represents a sequence of actions to be executed This sequence runs from left to right and from top to bottom In order to create a workflow the user assigns actions to each 8 boxes by clicking on the box to be edited and clicking on the next to one of the actions located on the right hand side or directly on the action label i e Add descriptors Diagram Board amp Clear and restart the diagram Undo List of actions Setup protein for E Dock ligand s using E docking fitted ca a a te Hh y Predict som using metafitted E l K MS a Make protein similar Th Prepare protein pdb Y to mol2 ih Once the diagram is complete user makes it active and available in the job manager section The user created workflows become available to all the users on the platform There is no validation for the compatibility of the actions within the workflow The user needs to know which actions can be connected together see the actions section below JOBS MANAGER The job manager allows users to create a job based on a workflow The first step is to parameterize the job the second step is to execute the job and the final step is to visualize the results HOME WORKFLOWS MANAGER JOBS MANAGER FILE MANAGER SKETCHER REACTIONS SETTINGS Listing Jobs Add a new job 8 Job Manager help Search Sort by Date Created w Self Docking 1e2k self an docking
15. cking 1e2k self ae Prepare protein Status Completed close docking wf 1 bs pdb to mol2 SHOW PROGRESS Job completed 27 06 2013 00 49 AM Reset Job Ss Setup ligand s for ei Output docking results txt Structure docking _Complex pdb docking Start Date 2013 06 26 at 20 55 End Date 2013 06 26 at 20 58 4 Setup protein for docking OS Run Time Oh 3min 38sec Dock ligand s using FITTED SHOW PROGRESS PD 13 FILE MANAGER HOME WORKFLOWS MANAGER JOBS MANAGER FILE MANAGER SKETCHER REACTIONS SETTINGS User Files upload files to My Files folder File manager help search MY FILES MY_PROTEINS TEMP Y Personal folder by 5 Files by Temporary System Folders 13 Files Empty Self Docking WF 1 Self Docking WF 2 Doy 1e2k self docking Day Self Docking Jun 27 2013 00 58 53 10 Files Jun 27 2013 00 38 14 1 File The files in the file manager can be deleted or downloaded Users can also zip the entire folder or just several selected files In order to be visualized by the Open Astex Viewer plugin multiple mol2 files can be combined by clicking on the COMBINE mol2 icon This function assembles several mol2 files i e a protein and a docked ligand into a single file compatible with Open Astex Viewer The Icon and List View buttons allow users to change how they view their files FOLDER MY FILES Each user has a personal folder called My Files in which files from different jobs can be saved to be
16. cking the Enabled box the admin allows the new user to access the application 19 Add User First name Last name Gender Male Login Email Fassword Password confirmation Enabled e Admin E Cancel Save PLUGINS MANAGER The plugins interface allows users to modify simple information about existing plugins or to delete them Listing Plugins Add a new plugin New plugin from XML fv Ace g Add descriptors gt 3D Clean structure geometry 2 0 3 0 3 0 EDIT DELETE EDIT DELETE EDIT DELETE gt 3D Convert 2D to 3D xML Convert file formats ch Create combinatorial library 3 0 1 0 1 3 EDIT DELETE EDIT DELETE EDIT DELETE 4 Dock ligand s using FITTED Extract representative library Filter by descriptors 3 0 1 2 1 3 New actions programs can also be integrated into the application When creating a new plugin users define all the necessary parameters required for the plugin to work inside of a workflow such as name version and executable files ADDING NEW PLUGINS Users can add new plugins i e new actions by clicking on Add a new plugin and defining fields in the plugin interface In the example described below an action called convert file format will be created This action can next be used in any workflow This action uses babel as an executable and we would like to create a form to set it up when preparing jobs The created form is shown below while the preparation of this form and its implementa
17. eaction scheme to prepare a combinatorial library The reactants name are guessed by the interface as Setup reactants for combichem should be used in a preceding box as shown in the Figure below The reaction is defined and pre encoded via the reactions manager 33 Create combinatorial library Standard Mode Input Reactant 1 scaffold 1 mol2 y Input Reactant 2 scaffold 1 mol2 x R m ae Convert 2D to 3D Convert 2D to 3D Setup A for Setup HU for combichem combichem Create combinatorial library Clean Structure ADD FRAGMENTS TO MOLECULES This action is in development and not fully functional yet Contact us for more information PHARMACOPHORE IDENTIFICATION AND SEARCH This action uses the RESHAPES program which is a tool for 3D pharmacophore search It derives a set of weighted pharmacophores from known actives and uses these pharmacophores to identify potential active molecules in a library Both the actives and the library files need to be in 3D sdf or mol2 formats This new program is still in development beta I 8 Pharmacophore identification and search 1 p Wi Standard Mode Esp Actives reshape_test_actives sdf w gt Library to be screened reshape_test_library sdf w Output File Name potential_actives different from input file name g SUBSTRUCTURE SEARCH This action uses FINDERS to search for molecules featuring a given substructure within a database of
18. ed Upload Molecular Files brings a window with different possibilities such as drawing directly the molecule downloading from the web retrieving from the PDB database or performing a local upload Upload Molecular Files Editing Jobs Parameters Name test Workflow Se Description Draw Molecule Download from web Diagram Boar Download from Protein Data Bank Once the files are uploaded users can then configure actions In a workflow each action i e box outputs a result file which then becomes the input file for the following action As the file does not exist yet the job has not been run yet an internal predictor guesses the name of these files As a consequence the boxes should be configured from top to bottom 11 1 Setup ligand s for docking Standard Mode O Input File Ej Output File Name different from input file name Atomic partial charges MMFF e assignment Electronegativity equalization method Keep input file charges Advanced Mode TEON A pause feature is implemented which allows the user to stop the execution of a job before a specified action during the workflow so the output of an action can be visualized or edited The job can then be resumed in order to proceed to completion This sequence runs from left to right and from top to bottom The figure below shows an example where the job will stop after the Prepare protein pdb to mol2 actio
19. ein or the receptor prior to Filters library using descriptors and docking program FITTED docking with FITTED functional groups FA Add descriptors Be Extract representative library Create combinatorial library Adds descriptors molecular weight Performs clustering on the library and Generates new 3D library based on a presence of functional groups to small extracts representative molecules chemical reaction molecules WORKING WITH FORECASTER THE SECTIONS When on the home page the user can see the various sections i e workflows manager jobs manager appearing on the top Clicking on them can give access to the other functionalities as discussed below MOLECULAR Admin Admin D Discovering Molecules Home Contact Us FAQ LOGOUT HOME WORKFLOWS MANAGER JOBS MANAGER FILE MANAGER SKETCHER REACTIONS SETTINGS KA Forecaster Drug Discovery Suite WORKFLOW MANAGER The workflow manager shows existing workflows HOME WORKFLOWS MANAGER JOBS MANAGER FILE MANAGER SKETCHER REACTIONS SETTINGS Se Listing workflows Add a new workflow Docking 1 Docking 2 Self Dockin HE g g g a Show Workflow as Show Workflow Sl Show Workflow Virtual Screenin Lead Optimisation Combinatorial Chemistr E i EH Show Workflow EE Show Workflow EE Show Workflow Convert 2D To 3D Test New Reaction Scheme Preparation and Docking of a It allows users to v
20. erated output file outputmol2 ADDING NEW PLUGINS FROM XML Users can also create new plugins by uploading and editing their own xml files in the system They may do so by clicking on New plugin from XML Adding a plugin from xml means that users can import an existing or sample definition of a plugin and modify it according to their needs Add Plugin from XML XML definition file _Browse The platform provides a sample file to help in the integration process The file is located in the doc folder of the application Once an xml file is loaded the user gets the new plugin screen identical to the one that appears when a plugin is created from scratch 23 CONFIGURATIONS MANAGER The configurations manager can be found in the setting menu tab It allows the administrator to edit and create new configurations used in the platform DEFAULT SETTINGS The current settings define the file types that are recognized and can be opened by the application s text editor The default settings also identify the maximum file size that can be opened by the application without having to be downloaded The platform s administrator can add settings by clicking on Add a new configuration Listing configurations Add a new configuration text file extension max_file_size_to_open 1024 EDIT DELETE log txt out sdf mol EDIT DELETE SAVE DATABASE TO FIXTURES This option allows the administrator to store speci
21. fied database information into files called fixtures which is used to re create the database after an update of the platform This action saves information about the workflows jobs users plugins reactions and configurations that were modified since the first deployment EXPERIENCED USERS ONLY This will merge the current database values into fixtures for future database recreation Are you sure you want to do this buin En 24 ACTIONS Small Molecules 1 setup ligand s for ya docking A 2 add hydrogen to 2d Ligand based structures pan MrT 1 add descriptors A 3 convert 2d to 3d 3D ist of actions 2 filter by descriptors Y 4 clean structure b3D 3 combinatorial some Structure based Ebraries from 2d s zon reacta Fa for of 1 dock ligand s using E ade combichem in 3 PEE 4 search for Zn ed gt 2 pee som using E analoques a oR impacts ct a Pee eT o 2D p E y representative libra Proteins Nucleic acids P y i 6 combinatorial library gf arhar 1 make proteins Th a Tan ORI TRE EEE cr Other similar l 4 7 add fragments to Y 1 convert file formats 2 superpose protein Th molecules i ee identification and x ag m a ae 3 merge files setup protein for repar es pita y h 9 substructure search J eer US A number of actions are already integrated in the FORECASTER platform Details about these actions are given below STRUCTURE BASED DOCK LIGAND S US
22. hristopher R Corbeil Pablo Englebienne Constantin G Yannopoulos Laval Chan Sanjoy K Das Darius Bilimoria Lucille L Heureux and Nicolas Moitessier Docking Ligands into Flexible and Solvated Macromolecules 2 Development and Application of FITTED 1 5 to the Virtual Screening of Potential HCV Polymerase Inhibitors J Chem Inf Model 2008 48 4 pp 902 909 3 Christopher R Corbeil and Nicolas Moitessier Docking Ligands into Flexible and Solvated Macromolecules 3 Impact of Input Ligand Conformation Protein Flexibility and Water Molecules on the Accuracy of Docking Programs J Chem Inf Model 2009 49 4 pp 997 1009 4 Pablo Englebienne and Nicolas Moitessier Docking Ligands into Flexible and Solvated Macromolecules 4 Are Popular Scoring Functions Accurate for this Class of Proteins J Chem Inf Model 2009 49 6 pp 1568 1580 5 Roxanne Kieltyka Pablo Englebienne Johans Fakhoury Chantal Autexier Nicolas Moitessier and Hanadi F Sleiman A Platinum Supramolecular Square as an Effective G Quadruplex Binder and Telomerase Inhibitor J Am Chem Soc 2008 130 31 pp 10040 10041 37 6 Pablo Englebienne and Nicolas Moitessier Docking Ligands into Flexible and Solvated Macromolecules 5 Force Field Based Prediction of Binding Affinities of Ligands to Proteins J Chem Inf Model 2009 49 pp 2564 2571 7 Janice Lawandi Sylvestre Toumieux Valentine Seyer Philip Campbell Sabine Thielges Lucienne Juille
23. iew details of existing workflows and to create new ones Users can only edit and delete workflows that have been created in addition to the out of the box workflows The workflows can be edited and deleted only when they are not used by any job In the Figure below Docking 1 is hard coded and is given as an example by the developers and cannot be edited nor deleted workflow 1 was created by a user and can be edited modified and or deleted Docking 1 Workflow 1 Show Workflow a Show Workflow A EDIT DELETE To view the schematic details of an existing workflow click on Show Workflow ADDING A NEW WORKFLOW Clicking on the Add anew workflow icon allows the user to create a new workflow A window appears where the user enters a name and a description of the new workflow to be created Add Workflow Name Workflow 1 Description Cancel Save After clicking on _ Save the user may create a diagram that represents the flow of actions to be executed by clicking on Start the diagram BUILDING A WORKFLOW DIAGRAM A new workflow diagram is opened by clicking on Start the diagram Diagram Board Clear and restart the diagram Undo ee E Y AS User can add boxes and connectors to the diagram by clicking on the green arrows A A creates a split creates a merge t and create boxes above and below the current one By clicking on the ks icon the user can delete a box from the diagram Diagram Board Cle
24. ing LIGAND BASED Standard Mode Number of protein s Protein File 1 Macromolecule Number of Ligand s Ligand File 1 Ligand Cutoff Output File Name different from input file name Prepare for Keep files for later use Advanced Mode 1 Protein structure docking to rigid protein 1E2K_pro mol2 Protein 1Ligand 1E2K_pro mol2 7 process_protein Docking to flexible protein Yes No SHOW ADD DESCRIPTORS As described in ref 2 SMART can add descriptors that can be used for further filtering This action has been built from this program The ligand must be in 3D and have hydrogen atoms added when given to this action Formats such as sdf and mol2 are accepted and automatically detected by the action Within the add descriptors action a number of descriptors and functional groups are automatically identified and added as a bitstring in the resulting mol2 output file 30 1 Add descriptors a Standard Mode Y gt Input File Library sdf 3D sdf or mol2 y Input Format 2D sdf r Output File Name ligand different from input file name Advanced Mode FILTER BY DESCRIPTORS Filter by descriptors uses the descriptors prepared using the action mentioned above and keep only the molecules with the appropriate properties It uses the REDUCE program Descriptor Minimum Maximum Molecular weight D 500000 Net total charge
25. molecules when reacting with the CYP heme as the activated iron oxygen species It uses a significantly modified version of our FITTED docking program to predict CYP mediated metabolism of small molecules Advanced Mode 26 The action contains a single box the molecule can be drawn in 2D within the sketcher or uploaded as an sdf file A 3D format is also supported single or multi mol2 files The user can choose between the five implemented CYP 450 namely 1A2 2D6 2C9 2C19 and 3A4 or all five in a single run 2 Predict SOM using IMPACTS Standard Mode Input Output parameters P450 enzyme 209 Ligand File flurbiprofen mol Output File Name impacts_results different from input file name Advanced Mode PROTEINS NUCLEIC ACIDS MAKE PROTEINS SIMILAR This action takes multiple protein pdb files the proteins need to have greater than 90 sequence identity and perform a sequence alignment to superpose all the proteins together In a second step all the proteins are made similar by deleting or mutating amino acids to be identical to the first in the list the reference protein Corresponding pdb files are then obtained and can be used with the action Prepare pdb to mol2 If the sequence identify is too low an error message will be given and no structure produced 27 1 Make proteins similar Standard Mode 5 Number of protein s Protein File 1 s Chain s Protein File
26. n from which the protein in mol2 and the ligand in mol2 are generated 12 EXECUTING AND VIEWING JOBS Once a job is correctly setup it can be started The job manager allows users to monitor the job and as each action completes its execution color led will indicate its status Output files can be viewed as soon as they are available Self Docking 1e2k self Prepare protein ee Status docking wf 1 O pdb to mol2 i Job ready to run ab AA i andie f Structure Ed it parameters H Up BGAN SHOW PROGRESS docking Start Date StartJob e End Date Delete Job Setup protein for SHOW PROGRESS Run Time docking t Dock ligand s using SHOW PROGRESS FITTED Stand By close None Available None Available N A N A N A FILE PREVIEW Once a job is completed or running the resulting files can be viewed directly in the job manager unless the output is too large In this latter case the file should be viewed or downloaded in the file manager A job can be stopped or reset at any time to allow users to re parameterize and restart it at their convenience When a job is running a corresponding folder is created in the file manager where all input and output files are stored Each job belongs to a particular user and cannot be viewed by other users q docking results txt Listing Jobs Add a new job 8 Job Manager help Search Sort by Date Created x Self Do
27. o three dimensional mol2 files that can subsequently be used as inputs in workflows Convert 2D To 3D E SN Show Workflow Any molecule that is drawn and saved can later be loaded and reopened in the applet for viewing and editing 16 REACTIONS MANAGER The reactions manager is a tool that allows users to define reaction rules used in the Combinatorial Library from 3D Structures plugin This section is in its development phase we are currently improving the automated reaction rules definitions and developing REACT 2 0 now in beta version which will soon fully replace this first version CREATING REACTIONS Users have two options when it comes to creating new reaction rules They can either write the rules themselves or use the SketchEl java applet to draw the reaction After assigning a name to the new reaction user can add as many rules as he likes by clicking on S Addanew rule an q filling out the appropriate fields The rule number defines which reactant the rule applies to the rule name is usually the reactant functional group the center is the reacting atom center of the molecule the kept atoms are the atoms that remain in the product of the reaction the removed atoms are the atoms that are deleted by the reaction new atoms are atoms the atoms that are created by the reaction Once the reaction is defined and saved it can be used in the Create Combinatorial Library plugin HOME WORKFLOWS MANAGER JOBS MANAGE
28. os 36 SITUEtU re ODUM IZATION a peace sneaasharaeane nine eeaas paeanaeaberaeneans 36 OE gas sees A tases ace eee ace 36 CONVERT THE TO FINALS estuasts Saa 36 FUNCION MIKE coda 36 Retreat 37 INTRODUCTION The programs included in the FORECASTER Platform have been developed within the Moitessier group at McGill University Team leader Prof Nicolas Moitessier Development and support team leader Dr Eric Therrien http www molecularforecaster com support html Please refer to the FORECASTER platform by citing the following publication Therrien E Englebienne P Arrowsmith A G Mendoza Sanchez R Corbeil C R Weill N Campagna Slater V Moitessier N Integrating medicinal chemistry organic combinatorial chemistry and computational chemistry for the discovery of selective estrogen receptor modulators with FORECASTER a novel platform for drug discovery Journal of Chemical Information and Modeling 2012 52 1 210 224 Please refer to the FITTED program by citing the following publication Corbeil C R Englebienne P Moitessier N Docking ligands into flexible and solvated macromolecules 1 Development and validation of FITTED 1 0 Journal of Chemical Information and Modeling 2007 47 2 435 449 Please refer to the IMPACTS program by citing the following publication Campagna Slater V Pottel J Therrien E Cantin L D Moitessier N Development of a computational tool to rival experts in the prediction of sites of
29. rat Jeanneret and Nicolas Moitessier Constrained Peptidomimetics Reveal Detailed Geometric Requirements of Covalent Prolyl Oligopeptidase Inhibitors J Med Chem 2009 52 21 pp 6672 6684 38
30. rignard addition are not yet considered These issues will be addressed in the next version If the user cannot produce the rules using the applet the rules can be set manually Otherwise contact Molecular Forecaster info molecularforecaster com for the development of new rules Other limitations are regioselectivity if more than one functional group of a kind is found the first one will react and stereoselectivity it a chiral center is formed a single isomer is produced Stereoselectivity will be considered in the future 18 ADMINISTRATOR INTERFACE SETTINGS HOME WORKFLOWS MANAGER JOBS MANAGER FILE MANAGER SKETCHER REACTIONS SETTINGS Forecaster Advanced Settings wg Plugins Manager Users Manager Configuration Manager amp 4 a Save Database to Fixtures USER MANAGER The user manager is located under the settings menu tab It allows the administrator to manage users and their roles in the platform USER ROLES AND ACCESS Each user has a role that is assigned by the platform administrator Depending on their roles users are given authorization to access certain features of the program ADDING NEW USERS Only the program administrator can add or delete users and edit access settings for existing ones Listing Users Add a new user Admin Admin Guest User admin guest EDIT DELETE EDIT DELETE Clicking on the next to Add a new user allows the admin to create a new user By che
31. t programs and required by most actions in FORECASTER as shown below 28 an a 3 Prepare protein pdb to mol Standard Mode Number of protein s 1 Protein ts Protein File 1 1E2K pdb ase Output prepare protein Identify ligand residues Select pdb ts in pdb Number of ligand i ku residues Residue Name Chain Name Residue Number Residue 1 THC A 500 Re assign hybridization Mo a Protenate atom No Optimize a te Mo Iterations aade Generate new side chain zr arene conformations Take from input file only Water Molecules Crystallographic Macromolecule Protein aaa Advanced Mode es ILE hi AAA Errr When setting this action in job manager the user will have to provide the ligand name i e TMC A 500 below This information can be found in the pdb file By selecting the desired pdb file in the Identify ligand residues in pdb section Open Astex viewer will open and allow the user to click on the ligand and obtain the ligand residues code xTMC A 300 29 SETUP PROTEIN FOR DOCKING This action is required to prepare the necessary files for FITTED to work In the publications describing FITTED 1 3 we refer to the use of a program Process which is the core of this action It requires a protein mol2 file as input Providing a ligand mol2 file helps identifying the binding site The ligand file can be obtained by the action Prepare protein pdb to mol2 4 Setup protein for dock
32. the field This label will be used as label in the form Name specify internal field name in a single word no spaces Field type there are seven possible field types that can be defined Check box radio button or select when defining one of these field types the options must be specified in the value field separated by commas and the default option will be selected String or text is a text input to be filled out by the user File when this field type is defined a file is selected from a drop down menu containing a list of files uploaded to the job using the new plugin 22 Hidden a hidden field contains the keyword value that will be used and that cannot be modified by the user Mode fields can appear in the simple or the advanced mode The simple mode contains common parameters modified by most users Parameters that are less likely to be changed or that are used by more advanced users are placed in the advanced mode Keyword is the name that will be used in the keyword file It will be followed by the value selected or written in the field depending on the field type Mandatory specify whether or not filling out a field is mandatory Once the form is saved it can be used to edit parameters used in a job Convert molecules to different formats SIMPLE MODE Input format of the mal Molecule The input file 1hxk_lig_1 mol2 Output format of the molz molecule The gen
33. tion as an action is given in the subsequent section 20 Convert file formats SIMPLE MODE Format Input Input file Format Output Output file This form is associated to an action with a name an executable i e program and keywords or arguments if the executable uses a command line By clicking on Add a new plugin and defining the following window appears and needs to be filled Edit Plugin Plugin Name babel Unique identifier in the system with no spaces Version 1 0 Release version of the plugin eg 1 0 Function of the plugin Convert file formats What the plugin does Diagram box name babel Short description of the plugin function Active e Displays the plugin on the workflow Promote U Displays the plugin on the home page Description Convert different file formats Description displayed on the home page a o Yes Use system install Doi Plugin executable path c babel babel exe Yes Use keyword file D Each new plugin has to be assigned a unique name and version The function of the program may also be described Additional details about the plugin s purpose may be added in the diagram box name field Users can choose to promote the plugin by checking off the promote box which will ensure that the new plugin is shown on the home page A description of the plugin s function that will appear on the home page can also be added 21 If the plugin s executable file is located on the
34. with this action are mol and sdf 2D 3 Convert 2D to 3D Standard Mode Input File dd flurbiprofen mol Output File Name flurbiprofen3D different from input file Name Advanced Mode CLEAN STRUCTURE GEOMETRY This action cleans add missing hydrogens and optimizes the input structure s through energy minimization optional It requires 3D structure files mol2 or sdf SETUP REACTANTS FOR COMBICHEM IN 3D This action prepares the reactants for further processing with the program REACT implemented in the action below The dialog box is similar to the action add descriptors It requires 3D structure files mol2 or sdf STRUCTURE OPTIMIZATION This action optimizes structures that have been setup for docking conjugate gradient minimization It requires 3D structure files mol2 or sdf OTHER CONVERT FILE FORMATS This action uses babel to convert a structure from one format i e mol2 to another one i e sdf FUNCTION LINKER This is not a real action This action adds a connector i e a vertical bar to the workflow 36 Superpose Proteins Pdb to mol2 J Merge Files Setup protein Setup ligand s 1 j Docking with FITTED REFERENCES 1 Christopher R Corbeil Pablo Englebienne and Nicolas Moitessier Docking Ligands into Flexible and Solvated Macromolecules 1 Development and Validation of FITTED 1 0 J Chem Inf Model 2007 47 2 pp 435 449 2 C
Download Pdf Manuals
Related Search