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Keywords:

  • drug design;
  • conformational search;
  • pharmacophore;
  • protein–ligand docking;
  • database screening

Abstract

Computational tools have greatly expedited the pharmaceutical drug design process 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 conformation and a prescribed pharmacophore. The pharmacophore expresses constraints on the 3D structure of the molecule by specifying relative atom positions that should be maintained to increase the likelihood that the molecule will bind with the receptor site. This article presents a pharmacophore-based 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 identification 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 candidates. © 2000 John Wiley & Sons, Inc. J Comput Chem 21: 731–747, 2000