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Article ID: 253 - Last Modified: December 17, 2012

Is it possible to treat tautomeric forms of a ligand as interchangeable when developing a pharmacophore model?

Starting with Phase version 3.1, you can treat tautomers as interchangeable. There are two ways of doing so:

1) By running the Develop Pharmacophore Model workflow from the command line. A detailed tutorial that takes you through the command-line pharmacophore generation is in: $SCHRODINGER/phase-vversion/tutorial/pharm_tutorial.pdf

In particular, in Section 1.5 it is shown that the tautomers and their conformations can be assigned to the same LIGAND_GROUP, and they will then be treated as interchangeable when perceiving common pharmacophores.

2) By using the Develop Pharmacophore Model panel in Maestro, and defining ligand groups. This feature is available in Suite 2011.

For earlier suites, you can do this in Maestro by using a LIGAND_GROUP options file and the environment variable SCHRODINGER_PHASE_OVERRIDE, as follows:

Before starting Maestro, set the environment variable SCHRODINGER_PHASE_OVERRIDE to point to a file (typically located in the $HOME directory), which contains the LIGAND_GROUP options (an example of such a file is given below). Then start Maestro from the same shell. When the 'Find Common Pharmacophores' job is launched, its startup script will see that SCHRODINGER_PHASE_OVERRIDE has been defined, so it will read the file that this variable points to, and add those options to the input file that Maestro creates.

An example of a Phase override file that would be used to group two pairs of tautomers:

#begin_phase_multiPartition
LIGAND_GROUP=5,6
LIGAND_GROUP=8,9
#end_phase_multiPartition

This means ligands 5 and 6 should be grouped and ligands 8 and 9 should be grouped. These numbers are the Maestro ligand IDs, which will be the row numbers in the Ligands table, as long as the table hasn't been sorted and ligands haven't been deleted. Groupings should be defined only among ligands that are in the active Pharm Set. Please note that since four active ligands have been grouped into two groups, there are now two fewer ligands in the active Pharm set, so that the number of actives to match when perceiving common pharmacophores will have to be reduced accordingly; if the total number of active Pharm set ligands was originally ten, this has now been reduced to eight.

Keywords: Phase, tautomers, common pharmacophore

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