A randomized kinematics-based approach to pharmacophore-constrained conformational search and database screening

Computational tools have greatly expedited the pharmaceutical drug design p rocess in recent years. One common task in this process is the search of a large Library for small molecules that can achieve both a low-energy confor mation and a prescribed pharmacophore. The pharmacophore expresses constrai nts on the 3D structure of the molecule by specifying relative atom positio ns that should be maintained to increase the likelihood that the molecule w ill bind with the receptor site. This article presents a pharmacophore-base d database screening system that has been designed, implemented, and tested on a molecular database. The primary focus of this article is on a simple, randomized conformational search technique that attempts to simultaneously reduce energy and maintain pharmacophore constraints. This enables the ide ntification of molecules in a database that are Likely to dock with a given protein, which can serve as a powerful aid in the search for better drug c andidates. (C) 2000 John Wiley & Sons,Inc.