Efficient database screening for rational drug design using pharmacophore-constrained conformational search

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 paper presents a pharmacophore-based database screening system that has been designed, implemented, and tested on a molecular database. The key ingredient in this system is a simple, randomized conformational search technique that attempts to simultaneously reduce energy and maintain pharmacophore constraints. This enables efficient 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.