[ VLS Intro | Start | Database Format | Preferences | Docking Project Table File | Run VLS in the Graphical User Interface | Parallelization | VLS Results | Post Screen Analysis | Interaction Lists | 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.dtb file. The fields in this file are described here: https://molsoft.com/addons/ftp/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 .dtb file to change their defaults. A full description of each field in the .dtb file can be found here https://molsoft.com/addons/ftp/man/dockTable.pdf

 
#>i DOCK1.i_maxHdonors 
5 
#>i DOCK1.i_maxLigSize 
500 
#>i DOCK1.i_maxNO 
10 
#>i DOCK1.i_maxTorsion 
10 
#>i DOCK1.i_minLigSize 
100 

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 VLS Job Parallelization on a Local Machine, Cluster or Cloud

[ Gui Jobs | Vls command line ]

13.1.7.1 Sending Multiple Jobs in the GUI.

In the GUI you can run the screening in parallel in the following ways.

• Setup the docking project.
• Check the docking preferences and the database scan preferences. If you are screening millions of chemicals it is usually a good idea to run a test screen of a smaller set so you can see the likely range of scores.
• Index the SDF file you wish to screen using Docking/Tools/Index Mol/Mol2 File/Database.
• Select the indexed database using Docking/Setup Batch Ligand/From Indexed Database.
• Docking/Run Docking VLS Batch and enter the number of CPU threads you wish to use on your local machine by entering the number in the Number of Parallel Jobs dialog window. For example if you have a 4 cpu machine with 2 threads each you could split your screening up into 8 parallel jobs.
• Then the docking will run. In your docking directory you will see multiple .ou file according to the number of parallel jobs you are runing.

Or there is a more interactive way as described below.

• Select Docking/Run Docking VLS Batch
• Select the Local VLS Batch option.
• 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 licenses (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.

Or if you have a queuing system installed on the machine you are running the GUI you can use the tab VLS via Queueing System and this will split the jobs p via the number of jobs you specify and submit the jobs.

13.1.7.2 Sending jobs via the command line.

To run vls on the command line on a server or cloud machine.

• Setup the docking project.
• Check the docking preferences and the database scan perferences. If you are screening millions of chemicals it is usually a good idea to run a test screen of a smaller set so you can see the likely range of scores.
• Index the SDF file you wish to screen using Docking/Tools/Index Mol/Mol2 File/Database.
• Select the indexed database using Docking/Setup Batch Ligand/From Indexed Database. Check that the path to the database is correct in the docking_project.dtb file - you might need to add the path in the fields shown below.

#>s dockCOX.s_dbFile
/home/molsoft/celebrex50.sdf
#>s dockCOX.s_dbIndex
/home/molsoft/celebrex50.inx

• Send the jobs using _dockScan.

13.1.8 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:

13.1.9 Post Screen Analysis

[ Sort Hitlist | Plot | Complex & H-bond Display | Calculate Properties | APF Cluster | Interaction Fingerprints ]

13.1.9.1 Sorting the compounds in your HITLIST

Compounds can be sorted according to their SCORE and other properties in the hitlist. To sort the table single click on the column header - see the tables section of this manual for more information about manipulating tables.

13.1.9.2 How to Plot Histograms and Scatterplots of VLS Data

The hitlist generated from docking or screening typically contains many columns with numerical data, such as Score, RTCNN score, MolWt, LogP, Number of H-bond donors/acceptors, and others. Visualizing relationships between these columns can be a powerful way to explore trends and prioritize compounds. For example you may want to plot Score (Physics-Based Score) vs RTCNN Score and select those with low values for each. See the data plotting section of the manual here.

13.1.9.3 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.

13.1.9.4 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 'hammer' button (top right of table) to open the Tools panel. Click on the drop down button next to the Property Expression button. The options include:

• Calculate charge of the ligands in the hitlist.
• Calculate Buried Surface Area (BSA) of the ligands in the hitlist. High BSA often correlates with stronger binding, because more of the ligand is making contact with the protein.
• Calculate volume change of the ligands in the hitlist. A large volume change may indicate that the ligand must distort significantly to fit in the pocket — this could come with an entropic penalty or strain, potentially lowering binding affinity. A small volume change implies the ligand fits well with minimal conformational adjustment — often a desirable trait.
• Calculate whether the ligand makes a hydrogen bond with a selection. Make a selection of the residue or atom in the receptor first. The function used in this scheme ranges from -2 to 0, where more negative values indicate stronger or more favorable hydrogen bonding interactions. This function is based on geometric criteria such as donor–acceptor distance and angle, and is designed to capture the typical energetic contribution of hydrogen bonds in molecular complexes. A value of 0 corresponds to no significant interaction, while a value approaching –2 reflects an optimal hydrogen bond geometry.
• 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. The fingerprint column is based on the list of interactions (see option described below) - it results in a column that can be clustered. Select the column and then click on the cluster button at the side of the hitlist.
• Calculate a list of the interactions. This option will produce a number of columns for each residue in the pocket resulting in '1' or '0' for h-bond donor, acceptor and apolar interactions.

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.

13.1.9.5 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.

13.1.9.6 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.

13.1.10 Interaction Lists

When analyzing docking results or receptor-ligand complexes in ICM, interaction lists provide a detailed view of the contacts between the ligand and nearby residues in the binding pocket.

In these lists, residues are labeled (1 or 0) according to their interaction type or property, helping you interpret their role in ligand binding:

• apo - Apolar. The residue interacts with the ligand through hydrophobic (non-polar) contacts, such as van der Waals interactions. These are important for stabilizing ligand binding through shape complementarity and desolvation.
• hba - Hydrogen bond acceptor. This residue accepts a hydrogen bond from a donor group on the ligand.
• hbd - Hydrogen bond donor. This residue donates a hydrogen bond to an acceptor group on the ligand.

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.