Pharmacophore Modelling: Methods,Experimental Verification and Applications
Arup K. Ghose, John J. Wendoloski · Kluwer Academic Publishers eBooks · 2005
1. The Concept of the Pharmacophore and its Validity The essential functionalities of a molecule necessary for its pharmacological activity are called pharmacophores. Although the idea of pharmacophores existed for a long time, Ehrlich [1] first introduced this terminology following the term chromophorewhich was used to describe the groups responsible for the color of a compound. The interest in the idea of pharmacophores has grown tremendously in the last few decades due to the availability of computer graphics [2], a number of computational methods to determine the pharmacophoric geometry [3‐7] and various software for 3D database mining using the concept of a pharmacophore pattern match [8]. However, the validity of a pharmacophore hypothesis came more from direct medicinal chemistry structure‐activity relationships (SAR) studies rather than from any theoretical calculations. Such calculations may be possible in the near future with the availability of an ever increasing number of ligand‐protein complex structures, better molecular mechanics force fields and better understanding of solvation factors. In such an approach, we have to show that the pharmacophoric groups provide the major contribution in binding affinity to the protein compared to the rest of the molecule. The main objective here is to discuss the various computational methods for pharmacophore identification and its geometry determination, a number of ways to validate the pharmacophore models and their applications in medicinal chemistry to identify novel active compounds. There are several excellent reviews and papers on pharmacophore modelling [3‐7]. 2. The Medicinal Chemistry Approach for Pharmacophore Determination and its use in Computational Chemistry