Catalyst Application Note
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Key Products
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Shikha Varma-O’Brien and Samuel Toba, Accelrys, Inc.
Any conformation generation algorithm for the purposes of pharmacophore
modeling needs to address two important points: adequate coverage of the
energy landscape and diversity represented among the conformational models of
the compound under consideration. Catalyst® allows conformation generation,
within a user-defined energy threshold, through either a FAST method or a BEST
method. The FAST method is a preferred method for generating Catalyst 3D
compound databases, whereas the BEST method is recommended for generating
conformers that would be used as input for developing automated hypotheses
(HipHop, HypoGen, and HipHop Refine).1
The BEST conformation generation method uses the Poling algorithm, which
attempts to generate diverse conformers in feature space.2
In a recently pub-
lished study, Kirchmair, et al. investigated Catalyst’s ability to generate biologi-
cally relevant conformers using 510 protein-ligand complexes obtained from the
PDB.3 This work represents the most comprehensive external review focused on
the quality of conformers generated in Catalyst and the effect of several parame-
ters (FAST vs BEST methods, maximum numbers of conformers generated, and
the choice of energy threshold).
The study reveals that the recommended settings of generating 255
conformers using the BEST method and a 20 kcal/mol produces conformations with
RMS of less than 1 Å to the X-ray structure of the ligand. Both FAST and BEST meth-
ods provide best fitting conformers with RMS < 1.50 in more than 80% of all cases
and with RMS < 2 in more than 93% cases. Commonly used force fields