Virtual Screening Workflow Panel

Note:

The Virtual Screening Workflow panel will be deprecated in future releases. It is more efficient to use Active Learning Glide on larger libraries instead of HTVS. We plan to retire GlideXP in future releases.

The Virtual Screening Workflow panel enables you to set up and run jobs to screen ligands against one or more targets. The workflow includes ligand preparation, filtering, and up to three docking stages with Glide, progressing from HTVS to SP to XP docking. For docking to multiple targets (ensemble docking), you can specify docking score offsets for each target.

To open this panel, click the Tasks button and browse to Receptor-Based Virtual Screening → Virtual Screening Workflow.

  • Using
  • Features
  • Additional Resources

Using the Virtual Screening Workflow Panel

This panel can be used to run the entire sequence of jobs in the Virtual Screening Workflow. The panel sets up the input files for LigPrep, QikProp, and Glide ligand docking and submits them to the selected host in order.

When you run the workflow, you can pregenerate Glide grids for the desired receptors, or generate grids from the Workspace structure. For more information on generating Glide grids, see the Receptor Grid Generation Panel topic.

The ligand files for the workflow can consist of 2D structures or 3D structures. If your ligands are already 3D structures in the appropriate ionization and tautomeric state, you can deselect the Prepare ligands option. This is usually the case if you are docking from a Phase database. If you supply 2D structures, you must run the ligand preparation part of the workflow to convert the structures to 3D for docking. This stage runs a LigPrep job, with the standard options for most parts of the LigPrep process. You can control some of these options, but if you want to use other options, you should run LigPrep on the ligands independently. For more information, see the LigPrep Panel topic, or the LigPrep User Manual. Because LigPrep does not sample conformations of 7-membered or larger rings, you can run a MacroModel job after LigPrep to sample these rings.

Prefiltering of the ligands can also be performed as part of the workflow. If you want to use the Lipinski Rule option, you must run QikProp to obtain the required properties. You can run QikProp as part of the workflow, regardless of the ligand source. If you have already run QikProp, you do not need to run it again. The reactive groups filter is a predefined filter that removes ligands with these groups. If you want to specify a custom filter, you can provide an input file for ligfilter, which will then filter the structures, or set up the filter in a graphical interface. You can also choose whether to filter the ligands before or after preparation. For more information on ligfilter, see the Ligand Filtering Panel topic or Filtering Structures by Property: ligfilter.

The full workflow includes three docking stages. The first stage performs HTVS docking. The ligands that are retained are then passed to the next stage, which performs SP docking; the survivors of this stage are passed on to the third stage, which performs XP docking. At each stage you can decide how many ligands are kept, and whether the ionization and tautomeric states of each ligand are kept.

The stages of the job are managed by a master job, and the work can be divided into subjobs, which can in turn be distributed over multiple processors. The master job runs locally, but you can specify hosts to run the ligand preparation (LigPrep) and grid generation and docking (Glide) and the number of processors to use on each host, in the Job Settings dialog box. For docking you can specify the number of subjobs, in the Separate into N subjobs text box, or select Adjust to automatically adjust the number of subjobs so that each takes between 1 and 10 hours. For effective load balancing of a distributed job, the number of subjobs should be several times the number of processors.

The workflow is intended to be robust, so that if a subjob fails, the master job attempts to rerun the job a few times before quitting.

If you want to incorporate the results in to the Maestro project, you can choose Append new entries from the option menu in the Output section of the Job Settings dialog box.

You can dock the ligands to multiple receptors in the workflow, and provide an offset for the GlideScore so that the results from different receptors can be compared. If you want to merge more results later, you can do this with the script $SCHRODINGER/utilities/glide_ensemble_merge. Use the -h option for the syntax of this script.

To write out the input file and a script for running the job from the command line, click the arrow next to the Settings button and choose Write. For information on command usage and options, see vsw Command Help.

Virtual Screening Workflow Panel Features


  • Input
  • Filtering
  • Preparation
  • Receptors
  • Docking

Input Tab Features

Source of ligands options

These options and the associated controls allow you to specify the source of the ligands:

Files option, text box and Browse button

Read the ligands from one or more files.

  • To specify ligand files, you can enter a comma-separated list of file names in the Files text box, or click Browse to navigate to and select the files.

  • To specify multiple ligand files with related names, you can use the wild card characters * 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 unrelated names, you can create a text file that contains a list of ligand file names, and specify this text file in the Input ligand file text box, or click Browse and navigate to it. This is useful if the files are in different directories.

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

There are two options for specifying how the files are used for subjobs:

Use input files directly for subjobs option

Use the input files directly as the input files for the subjobs, and run one subjob for each input file. Doing so is useful if your ligands are already split across files in a way that is suitable for running a distributed job efficiently. If you select this option, you can't check for duplicate ligands or create a unique property to identify compounds (a set of structures that could be ionization states or tautomers of the base structure). Both of these require processing of all ligands, which is avoided with this option.

Combine input files and redistribute for subjobs option

Read all the input files, process the structures to create unique titles and check for duplicates if requested, and redistribute the structures optimally for efficient subjob distribution. This option requires enough disk space to store a copy of the input files.

Phase database option, text box and Browse button

Extract the ligands from a Phase database. Specify the path to the database or click Browse and navigate to the database in the file selector that opens. Phase databases have the extension .phdb. Older databases (ending in _phasedb) must be converted first, with phase_database.

You can restrict the ligand set to the subset of the database specified in the Subset text box. Enter the path to the subset or click Browse and navigate to the database subset in the file selector that opens. The subset has the extension _phase.inp.

Identify unique compounds by options

These options enable you to specify a property that identifies distinct (unique) compounds. This property is used to associate structures that originate from the same compound (tautomers, ionization states), so that they can be eliminated or retained as a group in the docking process. You can control which states of a given compound are kept in the Docking tab. These options are not available until you have specified the ligand input.

Generating unique property for each input compound option

If the structures you have are all unique compounds, you can create a property and assign a unique value to each structure with this option. The value that is assigned is an integer.

Using existing property option and menu

If the structures contain different ionization states or tautomers of the same compound, you can choose the property used to identify compounds by selecting this option and choosing a property from the option menu. The property names are taken from the first structure in each file, and only those properties that exist in each file are presented. You should ensure that the property you choose exists for each structure in the file, not just the first. The option menu becomes available when a file with valid properties is specified.

Value subset file option, text box, and Browse button

Filter the input structures so that only those containing certain values for the selected property are docked. The values are specified in a text file, one value per line. Enter the file name in the text box, or click Browse and navigate to the file. This option is only available if you use an existing property for identifying unique compounds. You can define a more flexible filtering scheme using ligand properties in the Filtering tab.

Filtering Tab Features

Run QikProp option

Select this option to run QikProp after the ligand preparation is done. You must run QikProp if you want to prefilter the ligands using the Lipinski Rule, or use QikProp properties for custom filtering. If your ligand files already have QikProp properties, you do not need to run QikProp again; if they don't, select this option.

Prefilter by Lipinski's Rule option

Prefilter the ligands using Lipinski's Rule of 5 before docking. Ligands that do not satisfy this rule are not docked. This option requires QikProp properties. If the input structure files do not have QikProp properties, select Run QikProp in this tab.

Remove ligands with reactive functional groups option

Prefilter the ligands by removing ligands that have reactive groups. The filtering is done by ligfilter with a predefined set of reactive groups, which are:

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
Retain only ligands matching criteria options and buttons

Prefilter the ligands using ligfilter, retaining only those that match the criteria specified. To set up a custom filter or to read a filter file, click Criteria. This button opens the Ligand Filtering Panel, which creates a filter file containing the conditions that you set up for matching the ligands.

To clear the custom filter, click Clear.

Select Filter before preparation or Filter after preparation to determine at what point the criteria are applied.

Preparation Tab Features

Prepare ligands option

Select this option to prepare the ligands with LigPrep.

If your ligands are already 3D structures in the appropriate ionization and tautomeric state, you can deselect this option. This is usually the case if you are docking from a Phase database.

Regularize input geometries option

Regularize the input geometries, so that ligands that are identical apart from small deviations in the atom positions are always treated the same. This option uses a conversion to unique SMILES to ensure the same atom numbering and geometry. All atom properties are lost when you perform this conversion, but entry properties, including the title, are retained.

Remove duplicates option

When regularizing input geometries, remove any duplicates. The next three options apply when duplicates are removed.

Desalt option

Remove small molecules and ions from structures (as in LigPrep) before comparing structures for duplicates.

Neutralize option

Neutralize structures (as in LigPrep) before comparing structures for duplicates.

Merge properties option

Merge properties from duplicates. If the properties have different values, the property is converted to a string that lists the values.

Generate possible states at target pH text boxes

Generate ionization and tautomeric states that have significant probability in the given pH range. Enter the target pH and the range in the text boxes.

Using options

Select the program for generating states. Selecting Ionizer generates ionization states with the ionizer program, and tautomeric states with the tautomerizer program, separately. Selecting Epik generates ionization and tautomeric states with Epik at the same time.

Add Epik metal binding states option

Generate extra states that are suitable for binding to metals in proteins, using Epik. Only available when Epik is selected for state generation.

Remove high-energy ionization/tautomer states option

Select this option to remove ionization and tautomeric states that have high energies. These are states that are likely to have low populations at the prevailing conditions.

Obtain stereochemical information from options

These options allow you to specify the source of stereochemical information. If you have 3D structures, select 3D geometry to determine the stereochemistry from the geometry. Otherwise, select Specified 2D stereo properties, to use information from the stereochemical properties in the input file. Any stereochemical center whose chirality is not determined from this information will have its chirality varied.

Unspecified stereocenters text box

Enter the maximum number of stereoisomers to be retained by LigPrep in this text box. LigPrep generates up to 32 stereoisomers, which are then filtered to retain those with the lowest energies. Note that the LigPrep run preserves any existing chirality information in the input file, and selects starting chiralities based on the chemistry of naturally occurring steroids, fused rings and peptides.

Generate low energy ring conformations text box

Enter the maximum number of ring conformations to be generated by LigPrep in this text box. This does not include 7-membered and larger rings.

Enhance sampling of large rings using MacroModel option

Sample conformations of 7-membered and larger rings with MacroModel after ligand preparation. These ring conformations are not sampled by LigPrep.

Receptors Tab Features

Receptors for docking table

Lists the receptors to use for docking. You can select a single receptor in the table for editing. The receptors to be used can be managed using the buttons below the table. The table reports the ID that you assign to the receptor, the GlideScore offset that you provide, and the name of the grid file.

Add button

Add a receptor to the table. Opens the VSW - Receptor Dialog Box, in which you can either load a pregenerated receptor grid from file, or request the generation of a new receptor grid from the structure in the Workspace.

Edit button

Edit the information associated with the selected receptor. Opens the VSW - Receptor Dialog Box, in which you can either replace the receptor with a new receptor, or change information for the current receptor.

Delete button

Delete the selected receptor from the table. (No action is taken on any grids that have already been generated.)

Add Multiple button

Add multiple pregenerated receptor grids. Opens a file selector, in which you can browse to a location and select one or more grids. Once you have added the grids, you can edit them individually, by selecting a grid in the table and clicking Edit.

Align receptors option

Align receptors before generating grids, using the Protein Structure Alignment tool. This option does not align receptors for pregenerated grids, only those that are generated by the current VSW run. The receptors are aligned to the frame of reference of the first receptor in the table.

Docking Tab Features

Enhance planarity of conjugated pi groups option

Increase the torsional potential around bonds between atoms whose geometry should be planar (i.e. sp2 atoms). This option should make aromatic rings, amides, esters, and so on, less likely to adopt a nonplanar geometry.

Use Epik state penalties for docking option

Apply Epik ionization and tautomerization state penalties to the final docking score, and metal-binding penalties if they were calculated. This option is selected by default.

Write interaction scores for residues within N Å of grid center option and text box

Write per-residue interaction scores (score for interaction of the ligand with individual residues) for protein residues within the specified distance of the grid center. The cutoff must allow for the size of the active site. These scores can be displayed using the Pose Viewer Panel.

Scaling of ligand van der Waals radii for nonpolar atoms text boxes

Scale the van der Waals radii of ligand atoms by the factor given in the Scaling factor text box if the magnitude of the atomic partial charge is less than the value given in the Partial charge cutoff text box. The scaling simulates flexibility of nonpolar groups. For more information on the scaling, see the Glide Ligand Docking Panel DEPRECATED topic.

Dock with Glide HTVS option and Options button

Include a high-throughput virtual screening (HTVS) docking stage in the workflow. To change the default options for this stage, click Options, and make settings in the VSW - Docking Options Dialog Box.

Dock with Glide SP option and Options button

Include a standard precision docking stage in the workflow. To change the default options for this stage, click Options, and make settings in the VSW - Docking Options Dialog Box.

Postprocess with Prime MM-GBSA option

Run Prime MM-GBSA for the final poses to obtain the binding energy of the ligand. This task is performed at the end of the calculation for whatever docking stages have been selected.

Job toolbar

Manage job submission and settings. See Job Toolbar for a description of this toolbar.

The Job Settings button opens the Virtual Screening Workflow - Job Settings Dialog Box, where you can make settings for running the job.

Status bar

The status bar displays information about the current job settings and status for the panel. The settings includes the job name, task name and task settings (if any), number of subjobs (if any) and the host name and job incorporation setting. The job status can include messages about job start, job completion and incorporation.

Use the Reset button to reset the panel to its default settings and clear any data from the panel. You can also reset the panel from the Job toolbar.

The status bar also contains the Help button , which opens the help topic for the panel in your browser. If the panel is used by one or more tutorials, hovering over the Help button displays a button, which you can click to display a list of tutorials (or you can right-click the Help button instead). Choosing a tutorial opens the tutorial topic.

Related Topics