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 Virtual Ligand Screening
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PrevICM User's Guide
13.1 Virtual Ligand Screening

[ VLS Intro | Start | Database Format | Preferences | Docking Project Table File | Run VLS in the Graphical User Interface | PBS | Parallelization | VLS Results | Post Screen Analysis | Visualization ]

Available in the following product(s): ICM-VLS |

Additional Resources: Tutorial: Screen to Ricin Receptor | Tutorial: Screen to Cyclooxygenase | Tutorial: Screening a Markush Library | Command Line Docs | Video

13.1.1 Virtual Ligand Screening

Virtual Ligand Screening (VLS) in ICM is performed by docking a database of ligands to a receptor structure followed by an evaluation of the docked conformation with a binding-score function. Best-scoring ligands are then stored in the multiple icm-object file. The set-up of the VLS process is largely identical to the set-up for the small molecule docking simulation (see Small Molecule Docking section).

13.1.2 VLS Getting Started

Follow the instructions in the small molecule docking section manual from docking project setup option to the calculate maps option. Use Docking/Setup Batch Ligand option to select the database you wish to dock.

13.1.3 Database File Format

In most cases the ligand input file will be an SDF or MOL2 file. These files need to be indexed by ICM before they can be used in VLS runs. The index is used to allow fast access to an arbitrary molecular record in a large file such as an SDF file which in some cases contains over one million compounds.

To index an sdf file:

  • Click on the menu Docking/Tools/Index Mol/Mol2 File/Database to generate the index. The following data entry box will be displayed.

  • Enter the name of your Mol/Mol2 file and enter the name you wish to call your index file.
  • Select whether your file is in Mol or Mol2 format.

13.1.4 VLS Preferences

NOTE: It is important to setup the VLS preferences before undertaking VLS run. Additional preferences can be changed in the docking_project_name.tab file. The fields in this file are described here: ftp://ftp.molsoft.com/man/dockTable.pdf

VLS preferences can be setup by:

  • Selecting the menu Docking/Preferences/Database Scan

Different options are available to select by clicking the down arrow next to the data entry field. These options are described here:

Score Threshold:

An important parameter of the VLS run is the score threshold. Docked conformations for a particular ligand will only be stored by ICM VLS procedure if its binding-score is below the threshold. The choice of the threshold can be done in two ways: based on the scores calculated by docking known ligands. Generally, a value somewhat above typical score observed for known ligands is a good guess. If no ligands are known, a pre-simulation can be run using ~1000 compounds from the target database. Using the resulting statistics for the scores, the threshold should be set to retain ~1% of the ligands.

Potential of mean force score:

Potential of mean force calculation ( pmf ) provides an independent score of the strength of ligand-receptor interaction. The pmf-parameters are stored in the icm.pmf file.

Other selection criteria:

Other selection criteria which can be changed include

Minimum/Maximum Ligand Size you wish to be screened.

Maximum number of H-bond donors

Maximum number of H-bond acceptors

Maximum number of torsions

13.1.5 Docking Project Table File

ICM VLS uses a number of criteria to pre-select compounds before docking. Edit the project .tab file to change their defaults. A full description of each field in the .tab file can be found here ftp://ftp.molsoft.com/man/dockTable.pdf

#>i DOCK1.i_maxHdonors 
#>i DOCK1.i_maxLigSize 
#>i DOCK1.i_maxNO 
#>i DOCK1.i_maxTorsion 
#>i DOCK1.i_minLigSize 

13.1.6 Run VLS in the Graphical User Interface

First setup the docking project (From Set Project to Setup Batch Ligand)

To start the vls job:

  • Docking/Run Docking Batch

13.1.7 Running VLS Jobs in PBS UNIX Cluster Environment

Before VLS jobs can be run make sure you follow the instructions in the manual entitled Small Molecule Docking from docking project setup menu to the calculate maps menu. Select the "From indexed database", "From MolCart" or "From File: SDF/Mol2" option in the Setup Batch Ligand. Docking setup can be scripted see the terminal output from the GUI options to view the commands. More information on Docking and Virtual Screening using the command line can be found here http://www.molsoft.com/man/ligand-fit.html

13.1.8 Parallelization

If the database size exceeds several thousand compounds, it is desirable to run a number of VLS jobs in parallel to speed up the calculations. You can do this by choosing the Docking/Run Database Scan Batch option.

  • Select Docking/Run Database Scan Batch option
  • Select the local tab
  • Select the docking project name.
  • Enter the compound number you would like to dock from e.g. 8001
  • Enter the compound number you would like to dock to e.g. 10000
  • License type: For nearly all license (e.g. standard ICM-VLS licenses) types you need to leave this entry blank. If you have a -vlscluster license or a molvls license (-vls) then select the option from the drop down list. Any questions first check your license.dat file or Email support@molsoft.com.

On the command line using _dockScan (see: http://www.molsoft.com/man/ligand-fit.html):

the recommended way to run on multiple cores is just to launch several independent jobs on different database segments e.g.

icm _dockScan from=1 to=1000  > run1.ou &
icm _dockScan from=1001 to=2000 > run2.ou &
icm _dockScan from=2001 to=3000 > run3.ou &

Alternatively you can use proc=NCORES argument with a single run. This may have a bit higher overhead and slightly less robust (with single job, if it dies everything stops, with multiple jobs others keep going).

13.1.9 VLS Results

The easiest way to view the results of a VLS run is to make a hitlist. This was described earlier in the hitlist section of the small molecule docking chapter of the manual. Other ways of manipulating VLS data are described here:

13.1.10 Post Screen Analysis

[ Sort Hitlist | Plot | Histogram | Scatterplot | Complex & H-bond Display | Calculate Properties | APF Cluster | Interaction Fingerprints ] Sorting the compounds in your HITLIST

Compounds can be sorted according to their SCORE etc. See the tables section of this manual for more information about manipulating tables. How to Plot Histograms and Scatterplots of VLS Data

The hitlist contains many columns with numerical data. ICM can build interactive plots with the table columns (See Tables section). However, there are some easy to use plotting options in the docking menu which is described here. To construct a histogram of your VLS data

  • Select the menu Docking/Tools/Scan Results Histogram

  • Enter the name of the VLS output file (*.ou) you wish to construct a histogram for.
  • Select which paramater you wish to plot against frequency (see below).

  • Click OK and a def.eps file will be saved with a picture of your histogram. To construct a scatterplot of your VLS data

  • Select the menu Docking/Tools/Scan Results Scatterplot

  • Enter the name of the VLS output file (*.ou) you wish to construct a scatterplot for.
  • Select which paramater you wish to on the X axis.
  • Select which paramater you wish to on the Y axis.
  • Click OK and a def.eps file will be saved with a picture of your scatterplot. Hitlist - Make Complex and Display Hydrogen Bond

When you make the hitlist you will see a panel next to the chemical table called Tools. The options here can be used to:

  • Check the option display Hbonds if you would like to display hydrogen bonds when you browse the hitlist.
  • Check the option make complex structure if you would like the ligand-receptor complex to be displayed when you browse the hitlist. Post Screening Tools - Calculate Properties

There are a selection of property expressions associated with the ligands in the hitlist that can be calculated. To use these press the drop down button next to the Property Expression button. The options include:

  • Calculate charge of the ligands in the hitlist.
  • Calculate buried surface of the ligands in the hitlist.
  • Calculate volume change of the ligands in the hitlist.
  • Calculate whether the ligand makes a hydrogen bond with a selection. Make a selection of the residue in the receptor first.
  • Calculate pharmacophore RMSD. This property expression needs an object called 'pharma' loaded in the workspace, with the pharmacophore in it.
  • Calculate cisTransAmide Angle of the ligands in the hitlist.
  • Calculate distance to selection. Make a selection of the residue or atom in the receptor first.
  • Calculate non-overlap with selection. Make a selection of the residue in the receptor first.
  • APF pose similarity to a selected ligand. Make a selection of a ligand first.
  • Calculate and cluster the interaction fingerprints.

Each of these properties will be placed in the hitlist table as a new column. You can choose a column name before calculating using the Column name dialog box. Click on the Calculate property button to run the calculation. Cluster by APF Ligand Pose Similarity

Screening results in the hitlist can also be clustered by 3D pharmacophore chemical pose simialarity using Atomic Property Fields. To do this:

  • Make the hitlist (Docking/Make Hitlist)
  • Press the Cluster by APF button on the Tools panel (right hand side of hitlist table).
  • A tree will be displayed clustering the pose similarity of the compounds by APF fit.
  • The distance matrix is added to the hitlist. Interaction Fingerprints

An interaction fingerprint can help choose docked ligands with common interactions or a diverse set of interactions.The fingerprint is a bit string representing a contact with each atom. For specificity there is a special subset of bit strings which represent hydrogen bonding. An alternative to interaction fingerprints is to cluster by 3D pharmacophoric similarity using APF.

Step 1: Calculate Interaction Fingerprints
  • Setup and run the docking and then make a hitlist.
  • Optional: Make an orange selection of the ligand binding pocket. If no selection is made ICM will use the binding pocket as defined in the docking project.
  • Open the extra panel in the hitlist table.
  • Choose the option Interaction FPs in the Descriptor Calculator section of the panel.
  • Enter a name for the column.
  • Click calculate property.

Step 2: Once the calculation has finished a column will be added to the hitlist table.

Step 3: Cluster the Fingerprints
  • Select the fingerprint column.
  • Click on the cluster button.
  • Choose the options shown in the dialog window above.

Step 4: Select representative centers or conserved binding interactions.
  • Drag the distance bar to change the tree.
  • Click on the branches of the tree to select (use CTRL for non-contiguous selections).
  • Right click in "white space" and choose representative centers.

13.1.11 Post Screen Visualization

Once you have made a hitlist of the screening results you can use the panel on the right hand side of the hitlist to change visualization options. The available options are:

  • pocketSurface = The surface of the ligand binding pocket. White=aromatic lipophilic, Green=non-aromatic other (mostly aliphatic) lipophilic surface, Red=hydrogen bonding acceptor potential, Blue=hydrogen bond donor potential
  • pocketSkin = A skin representation of the neighboring residues.
  • Pretty = A default representation for ligand and receptor (see image below).
  • atomEnergies = An energy value for each atom in the ligand is displayed.Green and low numbers indicate a positive contribution to binding.
  • clashVolumes = Highlights any clashes between ligand and receptor.

Virtual Screening
Fragment Screening

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