virtual screening work flow

Virtual Screening Workflow

Virtual ScreeningWorkflow
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Virtual Screening Workflow 3

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The Virtual Screening Workflow is designed to run an entire sequence of jobs for screeninglarge collections of compounds against a particular target. The workflow includes ligand prep-aration using LigPrep, filtering using propfilter on QikProp properties or other structuralproperties, and Glide docking at the three accuracy levels, HTVS, SP, and XP. The designallows you to choose which of the stages to include in any run, and which selection of resultsfrom one stage are passed on to the next.

Before you run the workflow, you must ensure that receptor is properly prepared, and you mustgenerate Glide grids for the receptor. See the Protein Preparation Guide for information onprotein preparation, and Chapter 4 of the Glide User Manual for information on grid genera-tion.

The ligand files for the workflow can consist of 2D structures or 3D structures. If you supply2D structures, you must run the ligand preparation part of the workflow to convert the struc-tures to 3D for docking. This stage runs a LigPrep job, with the standard options for most partsof the LigPrep process. You can control some of these options, but if you want to use otheroptions, you should run LigPrep on the ligands independently. For more information, see theLigPrep User Manual.

Prefiltering of the ligands can also be performed as part of the workflow. If you want to use theLipinski Rule option, you must run QikProp to obtain the required properties. You can runQikProp as part of the workflow, regardless of the ligand source. If you have already runQikProp, you do not need to run it again. If you want to specify a custom filter, you can providean input file for ligfilter, which will then filter the structures. For more information onligfilter, see Section D.2 of the Maestro User Manual.

The full workflow includes three docking stages. The first stage performs HTVS docking. Theligands that are retained are then passed to the next stage, which performs SP docking; thesurvivors of this stage are passed on to the third stage, which performs XP docking. At eachstage you can decide how many ligands are kept, and whether all the ionization and tautomericstates of each ligand are kept, or only some.

The workflow is intended to be robust, so that if a subjob fails, the master job will attempt torerun the job a few times before quitting. If the master job fails (for example, due to a systemfailure or network failure) you can restart the job, and it will pick up the calculation from thelatest point for which it has results and can restart from them.



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The results of multiple runs of the workflow can be merged using the script $SCHRODINGER/utilities/glide_ensemble_merge. Use the -h option for the syntax of this script.

Running Schrödinger Software

To run any Schrödinger program on a UNIX platform, or start a Schrödinger job on a remotehost from a UNIX platform, you must first set the SCHRODINGER environment variable to theinstallation directory for your Schrödinger software. To set this variable, enter the followingcommand at a shell prompt:

Once you have set the SCHRODINGER environment variable, you can start Maestro with thefollowing command:

$SCHRODINGER/maestro &

It is usually a good idea to change to the desired working directory before starting Maestro.This directory then becomes Maestro’s working directory. For more information on startingMaestro, including starting Maestro on a Windows platform, see Section 2.1 of the MaestroUser Manual.

To run remote jobs, you must have access to a hosts file, named schrodinger.hosts, thatlists hosts on which Schrödinger software is installed for execution. Details of setting up thisfile can be found in Chapter 2 of the Job Control Guide.

The Virtual Screening Workflow Panel

The Virtual Screening Workflow panel sets up the input files for LigPrep, QikProp, and Glideligand docking and submits them to the selected host in order.

To open the Virtual Screening Workflow panel, choose Virtual Screening Workflow from theWorkflows menu in the main window.

The main part of the Virtual Screening Workflow panel consists of two tabs for setting up virtualscreening jobs. The features of these tabs and how to use them are described in separatesections.

• General Tab• Docking Options Tab

Below the tabs is a row of buttons:

csh/tcsh: setenv SCHRODINGER installation-directory

bash/ksh: export SCHRODINGER=installation-directory



• Start—Write the input file and start the job. Opens the Start dialog box, in which you canset job parameters, including distributing jobs over multiple processors.

• Write—Write the input file but do not start the job. Opens a dialog box in which you canspecify the input file name, without the extension. This is the equivalent of the job namein the Start dialog box, and is used to construct file names.

• Reset—Reset all panel settings to their defaults

General Workflow Setup

In the General tab you activate the parts of the workflow that you want to perform—ligandpreparation, running QikProp, filtering, and docking—specify the input sources, and setoptions for ligand preparation.

In the top section of the General tab, you specify the file that contains the ligands to be docked,and ensure that each ligand is uniquely identified. In the Prepare ligands section, you specifyoptions for LigPrep. The Filtering section allows you to run QikProp and filter the ligands byproperty. Finally, the Perform Glide docking section allows you to specify the grid for docking.

Specifying the Input Ligand Files

To specify a single ligand file, you can enter a file name in the Input ligand file text box, or clickBrowse to navigate to the file.

If you want to specify multiple ligand files with related names, you can use the wild card char-acters * and ? in the file name. These characters have their usual Unix file-matching meanings:? matches a single character, and * matches zero or more characters.

To specify multiple ligand files with any kind of name, you can create a text file that contains alist of ligand file names, and specify this text file in the Input ligand file text box, or clickBrowse and navigate to it.

If you type in the file name, you must press ENTER to ensure that the name is read and theUsing property option menu is populated.

Identifying Ligands and their States

In the docking sequence, you can choose to keep all the ionization and tautomeric states of agiven compound for which one of these states docks well. The ionization and tautomeric statesthat originate from the same compound are identified by their title. It is therefore necessary toset the title property. The controls under Create ligand titles to identify unique compounds by



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enable you to set or select the title for the ligands. The controls for setting the title are notavailable until you have specified the ligand files.

If the structures you have are all unique compounds, you can assign a unique title to each withthe first option, Giving each structure a unique title. The title that is assigned is an integer.

If the structures contain different ionization states or tautomers of the same compound, you canassign a title by selecting Using property and choosing a property from the option menu. Theproperty names are taken from the first structure in each file, and only those properties thatexist in each file are presented. You should ensure that the property you choose exists for eachstructure in the file, not just the first. The option menu becomes available when a file with validproperties is specified.

When the title is set, a new property is created to store the original title.

Preparing Ligands with LigPrep

If your structures are already 3D all-atom structures with the appropriate ionization and tauto-meric states, you do not need to prepare the ligands, and you can deselect the Prepare ligandsoption. Otherwise, ensure that this option is selected, and choose the desired options for gener-ation of states for each ligand.

To generate ionization (protonation) states that are likely to exist in a given pH range, enter thetarget pH and the range in the Generate states at pH text boxes. You can generate these stateswith either the Ionizer or Epik, by selecting the appropriate option. Epik is licensed separatelyfrom LigPrep; the Ionizer is included with LigPrep. In addition to varying the ionization state,LigPrep generates tautomeric states that are likely in the given pH range. You can removeionization and tautomeric states that have large penalties by selecting Remove high-energyionization/tautomer states. These are states that are likely to have low populations at theprevailing conditions.

The LigPrep run varies the stereochemistry, if it is not predetermined. Any existing chiralityinformation in the input file is preserved, and chemically reasonable chiralities are initiallyassigned for steroids, fused ring systems, and peptides. If you already have 3D structures, youcan select 3D Geometry for Obtain stereochemical information from to determine the stereo-chemistry from the structure. For the unspecified stereocenters, up to 32 stereoisomers aregenerated. These are ranked by energy, and only the lowest-energy stereoisomers are returned.You can control how many are returned by entering the number to return in the Unspecifiedstereocenters: retain up to N low-energy stereoisomers text box.

Ring conformations are varied by LigPrep. You can limit the number of ring conformationsreturned by entering the maximum number in the Sample 5/6 membered rings: retain up to Nconformations per ligand text box. This sampling does not include 7-membered and larger



rings, which can be sampled with MacroModel after ligand preparation by selecting Enhancesampling of large rings using MacroModel.

Filtering Ligands Prior to Docking

The Virtual Screening Workflow offers three choices for prefiltering ligands: prefiltering usingLipinski’s Rule of 5, removing ligands with reactive functional groups, and prefiltering with acustom filter. Ligands that do not meet the specified criteria are removed from the ligand listfor docking. Both prefiltering choices use ligfilter, which can filter the structures in aMaestro file based on any property in the file.

Figure 1. The General tab of the Virtual Screening Workflow panel.



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Filtering by Lipinski’s Rule

To prefilter the ligands using Lipinski’s Rule of 5, select Prefilter by Lipinski’s Rule. Ligandsthat do not satisfy this rule are not docked. This option requires QikProp properties. If the inputstructure files do not have QikProp properties, select Run QikProp.

Filtering Out Reactive Functional Groups

To filter out ligands that have reactive functional groups, select Prefilter by removing ligandswith reactive functional groups. The functional groups that are considered reactive are:

Filtering with Custom Filters

To set up your own filter, select Prefilter by custom criteria, then click Criteria to set up or readin the filter. The Filter options dialog box opens, which allows you to define the filtering criteriaor read a file containing filtering criteria.

Filters are constructed from a combination of criteria set for various Maestro properties,certain predefined feature counts, or counts of SMARTS patterns for functional groups. Eachligand must meet all of the criteria to pass through the filter.

• Acyl halides• Sulfonyl halides• Sulfinyl halides• Sulfenyl halides• Alkyl halides without fluorine• Anhydrides• Perhalomethylketones• Aldehydes• Formates• Peroxides• R-S-O-R• Isothiocyanates• Isocyanates• Phosphinyl halides• Phosphonyl halides• Alkali metals• Alkaline-earth metals• Lanthanide series metals• Actinide series metals• Transition metals

• Other metals• Toxic nonmetals• Noble gases• Carbodiimides• Silyl enol ethers• Nitroalkanes• Phosphines• Alkyl sulfonates• Epoxides• Azides• Diazonium compounds• Isonitriles• Halopyrimidines• 1,2-Dicarbonyls• Michael acceptors• Beta-heterosubstituted carbonyls• Diazo compounds• R-N-S-R• Disulfides



Figure 2. The Filtering Options dialog box, showing the Predefined tab.

The criteria are set by selecting an item from the list in one of the tabs, selecting a relationaloperator, and setting a value, then clicking Add. The criterion is added to the list at the bottomof the panel. You can delete a criterion by selecting it and clicking Delete. When you haveadded all the desired criteria, click OK to accept the filter.

To read a filter, click Read criteria file, and navigate to the desired file in the file chooser thatopens. The file must have the extension .lff. When you click OK, the file is read and thecriteria are listed in the Filtering definitions and criteria text area. You can then add criteria tothe list, or delete criteria from the list.

In the Properties tab, all properties that are defined in the input files for each ligand are listed.You can display properties by family (this includes product families, such as QikProp) to limitthe range of properties available, by choosing the family from the Show family option menu.

In the Patterns tab, you can create a new pattern by clicking New and selecting or enteringpatterns in the Add definition dialog box. This dialog box provides tools for including orexcluding patterns: ligands must match included patterns, but must not match excludedpatterns. A complex pattern can thus be built up out of simple patterns. You can choose fromthe existing patterns, or enter your own SMARTS pattern, then click Include or Exclude to add



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the pattern to the definition. The pattern is added to the list in the lower half of the dialog box.You can delete patterns from this list by selecting them and clicking Delete. To view the defini-tion of an existing pattern, select the pattern and click View definition. To complete the patterndefinition, enter a name in the Name of new pattern definition text box at the top of the dialogbox, and click Add.

Setup for Glide Docking

If you want to dock the ligands that you have prepared and filtered, you must specify one ormore grids for the receptor. The ligands will be docked to each receptor that you specify. If youdo not specify any receptors, the ligands will be prepared and filtered, but not docked. Thetools for doing so are at the foot of the General tab.

To add a receptor to the list:

1. Click Add.

The Add Receptor dialog box opens (Figure 3).

2. Enter the receptor grid base name, or click Browse and navigate to the grid file.

3. Enter a unique identifier in the Unique identifier text box. (The default is a single letter.)

Figure 3. The Add Receptor dialog box



4. Enter a value in the Glide score offset text box, if you want to shift the GlideScores forthis receptor.

5. Select constraints from the table by clicking in the Use column, if you want to apply con-straints.

Constraints are listed in the table if the grid was generated with constraints defined. OnlyH-bond and metal constraints can be used, even if others are present.

6. Click OK.

The receptor is listed in the table at the foot of the panel. If you want to change any data asso-ciated with a receptor, click Edit, and make changes in the Edit Receptor dialog box. Thisdialog box is the same as the Add Receptor dialog box (apart from the title). If you want toremove receptors from the table (and thus not use them), select the receptors and clickRemove.

Setting Docking Options

If you specified grids in the General tab, you can choose which of the three docking accuracylevels to include and set various options for docking in the Docking Options tab. The dockingoptions are described in detail in Chapter 5 of the Glide User Manual.

Setting Ligand Parameters

At the top of the Docking Options tab are two text boxes that specify cutoffs for the size of theligands and the number of rotatable bonds. Ligands larger than the specified number of atomsor with more rotatable bonds than the number specified will not be docked. See Section 5.3.3of the Glide User Manual for more information.

You can also soften the nonpolar part of the ligand potential, by scaling the van der Waals radiiof ligand atoms with small partial charges. To do so, enter the scaling factor and the partialcharge cutoff in the text boxes in the Scaling of ligand van der Waals radii section. SeeSection 5.3.4 of the Glide User Manual for more information.

Setting Up the Docking Steps

The lower part of the Docking Options tab allows you to choose which Glide docking runs toinclude in the workflow, and contains options for HTVS, SP, and XP docking runs. To includea docking run in the workflow, select the corresponding option. Under each option is a set ofcontrols for the docking stage. A common set of controls is provided for each option, whichare described below. In addition, there are mode-specific options, which are described after thecommon controls.



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Figure 4. The Docking Options tab of the Virtual Screening Workflow panel.

Common Controls

To apply constraints for the docking stage, select Use selected constraints for each grid.

The Amide bonds option menu enables you to specify how to treat non-planar amide bonds.The options to choose from are:

• Vary amide bond conformation—Allow non-planar conformations, without a particularpenalty.

• Retain original amide bond conformation—no variation of the conformation is permitted.



• Penalize non-planar conformation—Apply a penalty to nonplanar amide bonds.

The two Keep options allow you to specify the percentage (upper text box) or number (lowertext box) of the best compounds to keep. A “compound” may consist of several ionization ortautomeric states, as generated by LigPrep. The option menu allows you to choose how manyionization or tautomeric states to keep for each compound.

The options to choose from are:

• All states (default for HTVS)• All good scoring states (default for SP)• Only best scoring states (default for XP)

The rationale for keeping all ionization and tautomeric states is that the actual state that scoresbest can vary with the accuracy level. Keeping all states of a particular compound in the earlystages ensures that the structures that will score best in later stages are not discarded.

Specific Controls

There are four options for the docking method for SP docking: Dock flexibly, Dock rigidly,Refine, and Score in place. These are also available for XP docking, with the exception of Dockrigidly.

For XP docking there are three additional options:

• Generate multiple input conformations—Run a MacroModel conformational search jobon the input structures corresponding to the best poses from the previous stage to locatethe lowest-energy conformer, using two different force fields. This option generates twoextra input structures for XP docking, and therefore takes several times as long as an XPdocking run with a single structure (including the conformational search). The variationsin the input structures often produce better final results.

• Write XP descriptor information—This option writes the descriptor information neededfor the XP Visualizer, and requires a license for this feature. See Section 6.3 of the GlideUser Manual for information on the XP Visualizer.

• Postprocess with Prime MM-GBSA—Run a Prime MM-GBSA calculation on the finalposes to obtain ligand binding energies.



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Running Jobs

When the general setup and the docking setup has been completed, click Start to open the Startdialog box, in which you can set job options and start the job. The run consists of a main joband a set of subjobs. The main job starts all the subjobs for the various stages of the workflow,and collects the results.

You can choose separate hosts for the main job and the subjobs. The host you choose for themain job must have access to the input files and the current directory, but the host you choosefor the subjobs does not need access to these files and directory.

Each stage of the workflow can be divided into a set of subjobs, which can be run concurrently.You can specify the number of subjobs in the Separate into N subjobs text box. You shouldconsider all stages of the workflow when deciding on the number of subjobs. The main jobmay adjust the number of subjobs to better balance the load for each part of the workflow, sothe number you enter is a target, not a requirement.

If you run multiple subjobs you can select a multiprocessor host such as a cluster from theSubjob host option menu. This host need not be the same as the main job host. You can alsochoose to limit the number of processors allocated to the subjobs by entering the maximumnumber in the Distribute subjobs over n processors text box. The number of processors shouldnot be more than the number of subjobs. Otherwise, you can ensure that the maximum numberof processors available is allocated to the execution of the subjobs by selecting Distributesubjobs over maximum available processors.

Jobs can be monitored and controlled from the Maestro Monitor panel.

Output Files

Output files are created in subdirectories of the working directory. The path to the output filesis given at the end of the log file. For each receptor, a pose viewer file (_pv.mae) is created,containing the receptor and the docked ligands. In addition, the docked ligands are merged intoa single file, with properties resulting from the merge, including the GlideScore offset, thereceptor used, and the adjusted score. The merge is done by the glide_ensemble_mergeutility, which is described below. The receptors are also placed in a single file.

Merging Results of Multiple Jobs

Although you can include multiple receptors in a single run of the workflow, you may want tomerge the results of several runs of the workflow into a single Glide pose viewer file. You cando this with the utility glide_ensemble_merge. In the process, you can specify a scoring



offset for calibration of different runs. The results need not be from a single receptor: you canmerge results for multiple receptors. The script combines sorted Glide pose viewer(*_pv.mae) files into an output file, sorted by GlideScore.

The syntax is as follows:

$SCHRODINGER/utilities/glide_ensemble_merge [options] {-j jobname|--jobname=jobname} job1_pv.mae[:offset1] job2_pv.mae[:offset2][job3_pv.mae[:offset3] ... ]

The options are listed in Table 1. The list of files to be merged is a blank-separated list of pose-viewer file names. Each file name can be followed by a colon and an offset. The default offsetis zero.

Citing the Virtual Screening Workflow in Publications

Schrödinger Suite 2007 Virtual Screening Workflow; Glide version 4.5, Schrödinger, LLC,New York, NY, 2006; LigPrep version 2.1, Schrödinger, LLC, New York, NY, 2006; QikPropversion 3.0, Schrödinger, LLC, New York, NY, 2006.

Table 1. Options for the glide_ensemble_merge utility.

Option Description

--version Display program version number and exit

-h, --help Display usage message and exit

-n maxlig,--nreport= maxlig

Maximum number of best ligands to keep after merging. Default: 10000.

-j jobname,--jobname= jobname

Job name. Required. The output file is named jobname_pv.mae.


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Getting Help

Schrödinger software is distributed with documentation in PDF format. If the documentation isnot installed in $SCHRODINGER/docs on a computer that you have access to, you should installit or ask your system administrator to install it.

For help installing and setting up licenses for Schrödinger software and installing documenta-tion, see the Installation Guide. For information on running jobs, see the Job Control Guide.

Maestro has automatic, context-sensitive help (Auto-Help and Balloon Help, or tooltips), andan online help system. To get help, follow the steps below.

• Check the Auto-Help text box, which is located at the foot of the main window. If help isavailable for the task you are performing, it is automatically displayed there. Auto-Helpcontains a single line of information. For more detailed information, use the online help.

• If you want information about a GUI element, such as a button or option, there may beBalloon Help for the item. Pause the cursor over the element. If the Balloon Help doesnot appear, check that Show Balloon Help is selected in the Help menu of the main win-dow. If there is Balloon Help for the element, it appears within a few seconds.

• For information about a panel or the tab that is displayed in a panel, click the Help buttonin the panel. The help topic is displayed in your browser.

• For other information in the online help, open the default help topic by choosing Helpfrom the Help menu on the main menu bar or by pressing CTRL+H. This topic is dis-played in your browser. You can navigate to topics in the navigation bar.

If you do not find the information you need in the Maestro help system, check the followingsources:

• Maestro User Manual, for detailed information on using Maestro• Maestro Command Reference Manual, for information on Maestro commands• Maestro Overview, for an overview of the main features of Maestro• Maestro Tutorial, for a tutorial introduction to basic Maestro features• Glide User Manual, for detailed information on using Glide• LigPrep User Manual, for detailed information on using LigPrep• QikProp User Manual, for detailed information on using QikProp• Frequently Asked Questions pages on the Schrödinger Support Center.


https://www.schrodinger.com/SupportCenterMain.php?mID=8&sID=10&cID=0

Getting Help

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The manuals are also available in PDF format from the Schrödinger Support Center. Informa-tion on additions and corrections to the manuals is available from this web page.

If you have questions that are not answered from any of the above sources, contact Schrödingerusing the information below.

E-mail: [email protected]: Schrödinger, 101 SW Main Street, Suite 1300, Portland, OR 97204Phone: (503) 299-1150Fax: (503) 299-4532WWW: http://www.schrodinger.comFTP: ftp://ftp.schrodinger.com

Generally, e-mail correspondence is best because you can send machine output, if necessary.When sending e-mail messages, please include the following information:

• All relevant user input and machine output• Virtual Screening Workflow purchaser (company, research institution, or individual)• Primary Virtual Screening Workflow user• Computer platform type• Operating system with version number• Glide, LigPrep, and QikProp version numbers• Maestro version number• mmshare version number

Most of this information can be obtained under UNIX by entering $SCHRODINGER/machid in aterminal window.


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