Pharmacophore in Drug Design and Discovery

R.A. Hajare, S.T. Landge, V. M. Darvhekar, A.V.Chandewar

Abstract: A pharmacophore model is a geometrical description of the chemical functionalities required of a ligand to interact with the receptor. The key goal of computer-aided molecular design methods in modern medicinal chemistry is to reduce the overall cost associated with the discovery and development of a new drug, by identifying the most promising candidates to focus on the experimental efforts. Often, drug discovery projects have reached already a well-advanced stage before detailed structural data on the target has become available. Experimental screening for lead structure determination suffers from limitation with respect to the possible number of compounds that can be submitted to a high-throughput bio-assay and with the low number of hits obtained that is in the range of 0.1%. Within this context, the pharmacophore approach has proven to be successful, allowing (i) the perception and understanding of key interactions between a target and a ligand and (ii) the enrichment of hit rates obtained in experimental screening of subsets that have been obtained from in silico screening experiments.

Introduction: The pharmacophore is the group of these properties that form a vital part of a drug. A Pharmacophore may be defined as the essential geometric arrangement of atoms or functional groups necessary to produce a given biological response. The strict IUPAC definition of a pharmacophore is: A pharmacophore is the ensemble of steric and electronic features that is necessary to ensure the optimal supramolecular interactions with a specific biological target structure and to trigger (or to block) its biological response. Pharmacophore mapping is one of the major elements of drug design in the absence of structural data of the target receptor. The tool initially applied to discovery of lead molecules now extends to lead optimization. Pharmacophores can be used as queries for retrieving potential leads from structural databases (lead discovery), for designing molecules with specific desired attributes (lead optimization), and for assessing similarity and diversity of molecules using pharmacophore fingerprints. It can also be used to align molecules based on the 3D arrangement of chemical features or to develop predictive 3D QSAR models. This review begins with a brief historical overview of the pharmacophore evolution followed by coverage of the developments in methodologies for pharmacophore identification over the period from inception of the pharmacophore concept to recent developments of the more sophisticated tools such as Catalyst, GASP, and DISCO. In addition, we present some very recent successes of the widely used pharmacophore generation methods in drug discovery.



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