Jun 5 2018
[ 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 ]
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).
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.
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:
VLS preferences can be setup by:
Different options are available to select by clicking the down arrow next to the data entry field. These options are described here:
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
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 5 #>i DOCK1.i_maxLigSize 500 #>i DOCK1.i_maxNO 10 #>i DOCK1.i_maxTorsion 10 #>i DOCK1.i_minLigSize 100
First setup the docking project (From Set Project to Setup Batch Ligand)
To start the vls job:
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
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.
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).
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:
Compounds can be sorted according to their SCORE etc. See the tables section of this manual for more information about manipulating tables.
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.
When you make the hitlist you will see a panel next to the chemical table called Tools. The options here can be used to:
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:
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.
Screening results in the hitlist can also be clustered by 3D pharmacophore chemical pose simialarity using Atomic Property Fields. To do this:
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.
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:
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