Forecaster – GUI User Guide 1.0
Contents
1. 28 Molecular weight 0 500000 Net total charge 20 20 Number of hydrogen bond acceptor s 0 1000 Number of hydrogen bond donor s 0 500 Total number of atoms 0 1000 Number of heteroatom s 0 1000 Number of oxygen atom s 0 1000 Number of nitrogen atom s 0 1000 Number of sulphur atom s 0 1000 Number of metal atom s 0 0 Rings 0 1000 Number of rotable bond s 0 6000 Ionizable group s 0 200 None Filter Optional Min Max Acyl chloride a F Aldehyde a Amide a Ammonium a E Anilide a Aromatic a Azide a SETUP REACTANTS FOR COMBICHEM 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 CREATE COMBINATORIAL LIBRARY This action is based on our program React that takes two libraries of chemicals and a reaction 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 Create combinatorial library Standard Mode F Input Reactant 1 scaffold 1 mol2 x Fp Input Reactant 2 scaffold 1 mol2 EE 29 Convert 2D to 3D Convert 2D to 3D Setup reactants for Setup reactants for combichem combichem Create combinatorial library Clean Structure EXTRACT REPRESENTATIVE LIBRARY This action takes a library clusters the molecules by simil2. 0 Y Oy Setup ligand s for Setup protein for c a D A Dock ligand s using FITTED GO 7 A 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 9 Current job input files X O molecule mol X 7 2xpw pap Browse COPY from My Files Alternatively clicking on the container labeled 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 Ep Editing Jobs Parameters Current job input files gt Name test pO Browse Workflow Se Description 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 10 Setup ligand s for docking Input File 2XDW_lig mol2 w Standard Mode Output File Name molecule E different from input file name y Atomic partial charges MMFF
3. KA Forecaster Drug Discovery Suite WORKFLOW MANAGER The workflow manager shows existing workflows HOME WORKFLOWS MANAGER JOBS MANAGER FILE MANAGER SKETCHER REACTIONS SETTINGS a Listing workflows Add a new workflow Docking Docking 2 Self Docking Pp Show Workflow Pp Show Workflow pa Show Workflow Virtual Screening Lead Optimisation Combinatorial Chemistry PM Show Workflow po Show Workflow po Show Workflow Convert 2D To 3D Test New Reaction Scheme Preparation and Docking of a It allows users to view 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 Show Workflow gt EDIT DELETE To view the schematic details of an existing workflow click on Show Workflow ADDING A NEW WORKFLOW Clicking on the Add a new 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 c
4. assignment Electronegativity equalization method Keep input file charges ES Metabolism A pause feature is implemented which allows the user to stop the job after 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 action from which the protein in mol2 and the ligand in mol2 are generated Upload Molecular Files GO 7 A Dock ligand s using D A A 11 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 Docking 1 Locked Prepare protein Status Job ready to run O pdb to molz SHOW PROGRESS P Output i STEE Dens Edit Parameters ba on MANGLE er SHOW PROGRESS Start Job E Change Date Delete Job Fun Time lt Setup protein for docking SHOW PROGRESS w Dock ligand s using FIT Teo SHOW PROGRESS Standy By NA MA M 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 o
5. 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 Mame Field type Default Mode Value Keyword Mandatory 1 Inputformat Input_Forrnat select gt male simple Mode molt mol sdf pdb i Yes gt O Ee 2 2 The inputfile Input File File simple Mode Yes l E 3 QCutputtorm OutoutForme Select hd sat simple Mode mole mol sdf pdb o Yes a q The genera Output File string hd simple Mode hd es gt Cancel Save Order specify the order in which fields appear on a form Label describe 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 d
6. o EEE Aan EE Aaaa Taans 18 Adaine TOW WS Ol a aL 18 Puen Manan erdre a E re a eR re ee 19 Adaine NA ed 19 Adding Parametros 21 Adding new plugins Tom XM li 22 Conteurations Mandale T TAT A 23 Default SEN Syn is 23 Save Database CO FITUES vnin E a E N 23 ACTION a E E E E E E eee eee AE 24 Dock liigina kusine Fitted ean R 24 Prepare Drolet PG TO MO Za 25 SCUOTE Or COCKS aa 27 Setupleand s TOR GOGKING erea T a 27 AUCAS o E a A A E A 28 ICC OVCE SCAD OES tia 28 Setup reactants TOF combicie Misa ido 29 Create Combinatorial MIDE ia AA A 29 Extract representative Drar y sario 30 Search for analog UES ani 31 Predict SON USES IMPACTA 31 A O enn cements rem nore weary ae ne tach erat Cem Near creeper ne ear eae eae One ere sien eames 32 Convert O e lo 32 A A stoke eae stee nel oan eal aciecestealve dca eat a Scania teusne nce ccasatseents 32 Structure Optimi Zaton neser e T icGadarerniess coed raneancarnceaneeeane 32 Convertiile Tomate 32 Format Compatibility Table osa a 32 A pcs 34 DEVELOPMENT TEAM Team leader Prof Nicolas Moitessier nicolas moitessier mcgill ca Development and support team leader Dr Eric Therrien eric molecularforecaster com Developers Dr Nathanael Weill Dr Val rie Campagna Slater Andy Arrowsmith Hugo Boyer The programs FITTED SMART PROCESS SELECT REDUCE and REACT have been developed for the most part by Chris Corbeil PhD 2009 and Pablo Englebienne PhD 2009 as part of their graduate
7. studies The initial version of the platform FORECASTER has been developed by Sequence Technology Inc ImPAcTS was developed by Val rie Campagna Slater post doc 2011 Further developments and improvements are currently ongoing We thank other group members Janice Lawandi Stephane De Cesco Devin Lee Mitchell Huot Joris De Schutter Melanie Burger and Rodrigo Mendoza Sanchez collaborators and users for their valuable feedback Please refer to this platform by citing the following publication 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 Eric Therrien Pablo Englebienne Andrew G Arrowsmith Rodrigo Mendoza Sanchez Christopher R Corbeil Nathanael Weill Val rie Campagna Slater and Nicolas Moitessier Journal of Chemical Information and Modeling 2012 52 1 210 224 Contact info molecularforecaster com Website http www molecularforecaster com THE REGULAR USER INTERFACE 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
8. ETE EDIT DELETE EDIT DELETE gt 3D Convert 2D to 3D XML Convert file formats el Create combinatorial library 3 0 1 0 1 3 EDIT DELETE EDIT DELETE EDIT DELETE E Dock ligand s using FITTED a Extract representative library Y 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 implementation as an action is given in the subsequent section 19 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 versio
9. FORECASTER will display the login interface User inputs login name and password to log into the system LOGIN LOGIN PASSWORD 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 Eya Forecaster Drug Discovery Suite Dock ligand s using FITTED Th Setup protein for docking Y Filter by descriptors Docks ligand s using the automated Prepares the protein or the receptor prior to Filters library using descriptors and docking program FITTED docking with FITTED functional groups g Add descriptors k 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 MOV EEC U ECAR Admin Admin D Discovering Molecules Home Contact Us FAQ LOGOUT HOME WORKFLOWS MANAGER JOBS MANAGER FILE MANAGER SKETCHER REACTIONS SETTINGS
10. IDUE 504 B 400 SITE _IDENTIFIER AC3 EVIDENCE CODE SOFTWARE SITE_DESCRIPTION BINDING SITE FOR RESIDUE TMC A 500 SITE_IDENTIFIER AC4 EVIDENCE CODE SOFTWARE SITE_DESCRIPTION BINDING SITE FOR RESIDUE TMC B 500 RELATED ENTRIES RELATED ID 1KIM RELATED DB PDB ARG ALA PRO GLU LEU LEU ALA PRO ASN GLY ASP LEU TYR ASN VAL PHE ALA TRP ALA LEU ASP VAL LEU ALA LYS ARG LEU ARG SER MET HIS VAL PHE ILE LEU ASP TYR ASP GLN SER PRO ALA GLY CYS ARG ASP ALA LEU LEU GLN LEU THR SER GLY MET VAL GLN THR HIS VAL THR THR PRO GLY SER ILE PRO THR ILE CYS ASP LEU ALA ARG THR PHE ALA ARG GLU MET GLY GLU ALA ASN 5 5 18 18 S504 SULFATE ION TMC 1 4 HYDROXY 5 HYDROXYMETHYL BICYCLO 3 1 0 2 TMC HEX 2 YL 5 METHYLPYRIMIDINE 2 4 1H 3H 3 TMC DIONE 26 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 Setup protein for docking SIMPLE MODE F Number of protein s 1Protein w Protein File 1 1e2k_pro mol2 Use ligand to determine Yes binding site O No Ligand File 1e2k_lig mol2 x Ligand Cutoff 7 ADVANCED MODE SETUP LIGAND S FOR DOCKING In the publicati
11. MOLECULAR CUSTOMIZED WOF N DRUG DI DISCO VERY er com A 3 g Filter by Be AR Convert 2D to3D N Prepare protein pdb to mol2 Extract represen tative library i Create combinatorial library Search for analogues Easy i in tegration of 3rd party programs eS www molecularforecast bici 1 McGill Molecular Forecaster Inc Forecaster Platform 1 1 User Guide 21 February 2012 TABLE OF CONTENTS DEVELOPMENT TE Miastenia 4 The Reg lar USerIMteta cen san 5 Minimum requirements for clients iii die 5 LOEME ICE a EE E E EEE AA dica 5 HOMEN ON I O pesar N E E E 5 Working with OCC AS UCM agere paetcta des ares tocacacdaict dasteaaiededaiuiansne Ears E N ENE NASE AS AS 6 A o 6 ide alo AN as eee nee ee eee ere eer ee 6 Ss o rn e O 7 Building WoreHoOwWrala Saad 7 dE Ne E cee ss err eee aare nt asec e o Po 8 PUD SNOW OO ciara cece a te eat pacien 8 Editing the parameters and selecting the files to process oooccconcnccncnncnccnonancnnannnnninos 9 Exec ting and viewing OS singensorneosnaoie ata dc escenas 12 sn OI AA AE N saucer ses oaeaasioasce tenons 12 AL AA es se saa eo Es US E seas 13 FONG I CS motas 13 VOTO SI OCITIC F Ol OCIS omite 14 Aerea re i E OOO mem ere 14 RS e y q OPA CO E o E E 14 Savine ana OAC Tessa aa 15 REACTIONS Manager soii ia 15 Create aC TIONS suda 15 Administrator Interface Set Psico 18 uer IVa COR 18 User roles and ACCESS ssp eee enasemace tence sore
12. TED 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 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 Juillerat Jeanneret and Nicolas Moitessier Constrained Peptidomimetics Reveal Detailed Geometric Requirements of Covalent Prolyl Oligopeptidase Inhibitors J Med Chem 2009 52 21 pp 6672 6684 34
13. and editing REACTIONS MANAGER The reactions manager is a tool that allows users to define reaction rules used in the Create Combinatorial Library plugin This section might experience bugs we are still making improvements in the automated reaction rules definitions CREATING REACTIONS Users have two options when it comes to creating new reaction rules They can either write the rules themselves or use the ChemWriter 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 Add a new rule and 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 15 HOME WORKFLOWS MANAGER JOBS MANAGER FILE MANAGER SKETCHER SETTINGS Am o 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 c3 hn hn Remove Rule1 carboxylic_acid_al c3 0 o Remove Rule1 carboxylic_acid_ar c2 0 o Remove Rule1 carboxylic_a
14. arity and outputs a smaller library 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 Add descriptors Filter by descriptors Extract representative Prepare protein pdb library to mol2 Setup ligand s for Setup protein for docking docking Dock ligand s using FITTED 30 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 3DSDor3D SDF FORECASTER SHOW D 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 This action is not yet fully implemented in workflows Advanced Mode However it can be used alone PREDICT SOM USING IMPACTS This action uses the IMPACTS program predicts the most likely site s of reaction and transition state TS structures of small molecules when reacting with the CYP heme as the activated iron oxygen species lt uses a significantly modified version of our FITTED docking program to predict CYP mediated metabolism of small molecules The action contains a single box the molecule ca
15. cid_vi ca o o Remove Rule2 ammonium c3 hn hn hn Remove Rule ester c c3 0 os Remove aan ADD RULES FROM THE REACTION BELOW Alternatively users can draw and save each reactant and their product using ChemWriter click on Save all to save the drawn structures and have the rules generated automatically by clicking on 488 RULES From THE REACTION BELOW File Edit View Help File Edit View Help DOoO0o00oe gt Draw Product 1 File Edit View Help 16 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 found by the algorithm currently implemented Similarly reactions including two reacting atoms such as double bond reduction and metals Grignard 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 Stereoselect
16. er 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 22 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 1034 EDIT DELETE log txt aut sdf mol EDIT DELETE SAVE DATABASE TO FIXTURES This option allows the administrator to store specified 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 pr Be 23 ACTIONS List of actions Dock ligand s using fitted Predic
17. exible 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 fp Number of protein s 1 Protein structure docking to rigid protein Protein File 1 1e2k_pro mol2 w Number of Ligand s 1 Ligand Ligand File 1 te2k lig mol2 x Ligand Cutoff Output File Name different from input file name Prepare for Docking to flexible protein Advanced Mode lead 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 25 and finally outputs a protein file and a ligand file in mol2 format This format is appropriate for most programs and required by most actions in FORECASTER as shown below Prepare protein pdb to mol2 SIMPLE MODE EY Protein ej Output Number of ligand 1 i residues Residue Name Chain Name Residue Number TMC A 500 Optimize Iterations 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 SITE_IDENTIFIER AC2 EVIDENCE CODE SOFTWARE SITE DESCRIPTION BINDING SITE FOR RES
18. ivity will be considered in the future 17 ADMINISTRATOR INTERFACE SETTINGS HOME WORKFLOWS MANAGER JOBS MANAGER FILE MANAGER SKETCHER REACTIONS SETTINGS O Forecaster Advanced Settings bh Plugins Manager _ Users Manager Configuration Manager 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 checking the Enabled box the admin allows the new user to access the application 18 Add User First name Last name Gender Male Login Email Password Password confirmation Enabled e Admin O 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 DEL
19. lder or just several selected files In order to be visualized by the Jmol plugin multiple mol2 files can be combined by clicking on the COMBINE mol2 icon The Combine Mol2 function assembles several mol2 files i e a protein and a docked ligand into a single file compatible with Jmol 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 reused in other jobs It is used as a transfer folder between a given user s jobs MY FILES Personal folder 33 Files User Files upload files to My Files folder 8 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 Name w Filter by None 7 Files per page All w Page 7 MY FILES molecule mol 1 2 kb Y a 2xdw_lig mol2 le 6 2 kb 13 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 the system and it is at user s discretion to delete files contained in that folder MY FILES Self Docking WF 8 Personal folder Doy Self Docking 2 Files Sep 08 2011 15 55 45 2 Files FILES AND ACTIONS Files are viewed with different programs depending o
20. licking 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 Y Start the diagram Diagram Board Clear and restart the diagram Undo ma E PY 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 Y 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 Clear and restart the diagram Undo t Y it t 7 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 7 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 Clear and restart the diagram Undo List of actions Setup protein for E Dock ligand s using E docking fitted t Predict som using E metafitted k Make protein similar Th Prepare protein pdb Y to mol Eh 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 compa
21. n be drawn in 2D within the sketcher or uploaded A 3D format is also supported single or multi mol2 files The user can choose between the four implemented CYP 450 namely 1A2 2D6 3C9 and 3A4 Predict SOM using IMPACTS Standard Mode Input Output parameters P450 enzyme 2C9 Output File Name som different from input file name Protein flexibility mode Rigid enzyme x On Water Molecules off Advanced Mode CLEAN STRUCTURE This action cleans add missing hydrogens and optimizes the input structure s through energy minimization optional CONVERT 2D TO 3D This action takes the input structure s adds missing hydrogens converts from 2D to 3D and can optimize through energy minimization The file formats compatible with this action are mol and sdf 2d FUNCTION LINKER This is not a real action This action adds a connector i e a vertical bar to the workflow STRUCTURE OPTIMIZATION This action optimizes structures that have been setup for docking conjugate gradient minimization CONVERT FILE FORMATS This action uses babel to convert a structure from one format i e mol2 to another one i e sdf FORMAT COMPATIBILITY TABLE The following table gives details about which file formats are expected and compatible for the actions within Forecaster Actions Programs Input file formats Dock ligand s using Fitted mol2 fitted Predict som u
22. n 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 A iv Active vI Displays the plugin on the workflow Promote O Displays the plugin on the home page Description Convert different file formats Description displayed on the home page o Yes Use system install an Plugin executable path c babel babel exe Yes Use keyword file O No 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 20 If the plugin s executable file is located on the 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 plugins 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
23. n their type All text files are opened in a text editor directly integrated into the interface while mol2 files are visualized using the Jmol 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 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 ChemWriter java applet HOME WORKFLOWS MANAGER JOBS MANAGER FILE MANAGER SKETCHER REACTIONS SETTINGS Sketch your molecules Sketcher help File Name ES Save Merge With File 2xdw_lig mol2 x My Files molecule mol w e Load Mol Name a Merge File Edit View Help QS D O N IN DIOCIO OlO e gt 14 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 into three dimensional mol2 files that can subsequently be used as inputs in workflows Convert 2D To 3D t A E FS Show Workflow Any molecule that is drawn and saved can later be loaded and reopened in the applet for viewing
24. ons 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 sdf and mol2 formats are accepted and automatically detected by the action Setup ligand s for docking SIMPLE MODE Ep Input File 1e2k_lig mol2 Ej Output File Name lig MMFF Electronegativity equalization method Keep input file charges Atomic partial charges 2 assignment a SHOW Poma Ps ADVANCED MODE 27 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 Add descriptors Standard Mode 2 Input File Output File Name 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
25. own menu containing a list of files uploaded to the job using the new plugin 21 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 mol Molecule The input file 1hxk_lig_1 mol2 Output format of the molz molecule The generated output fle 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 Cancel The platform provides a sample file to help in the integration process The file is located in the doc fold
26. r 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 self docking results txt Listing Jobs Add a new job Job Manager help Search Sort by Date Created x Self Docking self docking Prepare protein e Status Completed close wf 32 pdb to mol2 Job completed Output self docking results txt 10 02 2012 17 03 PM l erent E docking Change Date 2012 02 10 at 12 13 Run Time Oh 3min 17sec ts Setup protein for docking SHOW PROGRESS 2 Dock ligand s using FITTED SHOW PROGRESS P 12 FILE MANAGER HOME WORKFLOWS MANAGER JOBS MANAGER File manager help Upload files to My Files folder MY FILES REACTOR FILES Personal folder Reactions molecules Ly f bj 34 Files bs 45 Files Create combinatorial library WF 12 FILE MANAGER SKETCHER Dy SETTINGS TEMP 35 Files Test new reaction scheme WF 14 Combi chem and docking test reductive amination May 11 2010 15 24 51 today s test 63 Files May 12 2010 08 45 29 8 Files Estrogen receptor WF 1 The files in the file manager can be deleted or downloaded Users can also zip the entire May 12 2010 09 07 19 11 Files fo
27. sing Impacts mol2 impacts Make protein similar Prepare pdb Prepare protein pdb Prepare pdb to mol2 Reconstruct protein Prepare pdb structures Setup protein for Process mol2 docking Superpose protein Prepare pdb structures Add descriptors Smart sd mol2 32 Output file format ligand mol2 sdf protein mol2 pdb mol2 pdb mol2 pdb mol2 pdb mol2 Clean structure Smart Minimize mol2 mol2 geometry Convert 2d to 3d Prepare Smart Minimize sdf mol mol2 Create combinatorial React mol2 mol2 library Extract representative Select mol2 mol2 library Filter by descriptors Reduce mol2 mol2 Search for analogues Select mol2 mol2 Setup ligand s for Smart sd mol2 mol2 docking Setup reactants for Smart sdf mol2 mol2 combichem Structure optimization Smart Minimize mol2 mol2 modified not standard mol file when flexible docking is performed the composite protein structure is provided in mol2 and pdb 33 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 Christopher 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 FiT
28. t som using 4 metafitted E Make protein similar MM Prepare protein pdb Eb to mol2 Reconstruct protein XML structures Setup protein for docking Superpose protein OP structures Th Add descriptors ga Clean structure Pap geometry Convert 2d to 3d 3D Convert file formats XML Create combinatorial r library Extract representative library Filter by descriptors y Search for analogues Eb Setup ligand s for docking A Setup reactants for combichem Structure optimization Ly Function linker Merge files A number of actions are already integrated in the FORECASTER platform Details about these actions are given below DOCK LIGAND S USING 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 24 Upload Molecular Files Upload Molecular Files Prepare protein pdb to mol2 Setup ligand s for Setup protein for ocking docking GC 7 A GC 7 A l Dock ligand s using DO A When setting this action in Job manager a few boxes have to be filled The number of proteins to be used in the fl
29. tibility 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 SETTINGS Listing Jobs Add a new job Test new reaction scheme testing various reactions Job ready to run 14 05 2010 20 40 PM Edit Parameters 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 SETTINGS Add Job Name Workflow Please Select Description 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 Name Self Docking x D 2xD5 pab B Workflow Self Docking pipi COPY from My Files Description Upload Files Diagram Board Upload Molecular Files F Prepare protein pdb to mol2
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