Predicting Molecular Interactions In Silico: I. An Updated Guide to Pharmacophore Identification and its Applications to Drug Design

Author(s): Oranit Dror, Alexandra Shulman-Peleg, Ruth Nussinov and Haim J. Wolfson

Pp: 551-584 (34)

Abstract

A major goal in contemporary drug design is to develop new ligands with high affinity of binding toward a given protein receptor. Pharmacophore, which is the three-dimensional arrangement of essential features that enable a molecule to exert a particular biological effect, is a very useful model for achieving this goal. If the three-dimensional structure of the receptor is known, pharmacophore is a complementary tool to standard techniques, such as docking. However, frequently the structure of the receptor protein is unknown and only a set of ligands together with their measured binding affinities towards the receptor is available. In such a case, a pharmacophore-based strategy is one of the few applicable tools.

Here, we present a broad, yet concise, guide to pharmacophore identification and review a sample of applications for drug design. In particular, we present the framework of the algorithms, classify their modules and point out their advantages and challenges.

Keywords: Pharmacophore mapping, pharmacophore modeling, ligand-based pharmacophore, receptor-based pharmacophore, pharmacophore fingerprints, virtual screening/kwd, >, pharmacophore searching, docking, de novo design, lead generation, computer-aided drug design