Pharmacophore Mapping: An Important Tool in Modern Drug Design and Discovery

Abstract

Computer-Aided Drug Design (CADD) has become an integral part of drug discovery and development efforts in the pharmaceutical and biotechnology industry. Since the 1980s, structure-based design technology has evolved, and today, these techniques are being widely employed and credited for the discovery and design of most of the recent drug products in the market. Pharmacophore-based drug design provides fundamental approach strategies for both structure-based and ligand-based pharmacophore approaches. The different programs and methodologies enable the implementation of more accurate and sophisticated pharmacophore model generation and application in drug discovery. Commonly used programmes are GALAHAD, GASP, PHASE, HYPOGEN, ligand scout etc. In modern computational chemistry, pharmacophores are used to define the essential features of one or more molecules with the same biological activity. A database of diverse chemical compounds can then be searched for more molecules which share the same features located at a similar distance apart from each other. Pharmacophore requires knowledge of either active ligands and/or the active site of the target receptor. There are a number of ways to build a pharmacophore. It can be done by common feature analysis to find the chemical features shared by a set of active compounds that seem commonly important for receptor interaction. Alternately, diverse chemical structures for certain numbers of training set molecules, along with the corresponding IC50 or Ki values, can be used to correlate the three-dimensional arrangement of their chemical features with the biological activities of training set molecules. There are many advantages in pharmacophore based virtual screening as well as pharmacophore based QSAR, which exemplify the detailed application workflow. Pharmacophore based drug design process includes pharmacophore modelling and validation, pharmacophore based virtual screening, virtual hits profiling, and lead identification. The current chapter on pharmacophores also describes case studies and applications of pharmacophore mapping in finding new drug molecules of specific targets.