Docking Studies in Drug Design and Discovery

R. A. Hajare*, D. W. Wargantiwar, A. V. Chandewar

Abstract: Docking studies are computational techniques for the exploration of the possible binding modes of a substrate to a given receptor, enzyme or other binding site. The application of computational methods to study the formation of intermolecular complexes has been the subject of intensive research during the last decade. It is widely accepted that drug activity is obtained through the molecular binding of one molecule (the ligand) to the pocket of another, usually larger, molecule (the receptor), which is commonly a protein. Computer assisted drug design has proved its utility during the last decades. One of its approaches consists in modeling the structure of an optimal receptor-ligand complex by testing different orientations for a set of small organic molecules, with pharmacological potential, into a presumed binding site in the receptor, generally a protein. This method known as docking. To decide for the best pose of a particular ligand, a numerical score was computed; the best one was selected, and compared with those from the other ligands. This score frequently rely on inter- and intra-molecular atomic interactions being electrostatics one of the main contributors to them. Consequently, it is of great importance to assign partial-charges accurately on the atoms of the ligand.
Pharmaceutical companies produce massive amounts of primary screening data for lead discovery. To make better use of the vast amount of information in pharmaceutical databases, companies have begun to scrutinize the lead generation stage to ensure that more and better qualified lead series enter the downstream optimization and development stages. Computational techniques for end to end analysis of large drug discovery screening sets. The analysis proceeds in three stages: In stage 1 the initial screening set is filtered to remove compounds that are unsuitable as lead compounds. In stage 2 local structural neighborhoods around active compound classes are identified, including similar but inactive compounds. In stage 3 the structure-activity relationships within local structural neighborhoods are analyzed.1
Computational techniques that can ‘dock’ small molecules into the structures of protein targets and ‘score’ their potential complementarity with putative binding sites have become popular in lead identification and optimization. Energy minimization or optimization is an important technique in molecular docking calculations. It is routinely used to optimize geometries within the binding site. Complex optimization allows the ligand to obtain minimum energy pose within the active site cavity of the protein. It also allow s the relaxation of protein to certain extent which can account for the conformational changes that happen in the protein structure on binding of the ligand. In addition the calculated energies can also be used to estimate the binding energy which help in quantifying the binding process and have better understanding of the molecular recognition.2 The free energy of binding is the change in free energy that occurs on binding, ΔG binding= G complex - G separated where G complex and G separated are the free energies of the complexed and no interacting protein and ligand respectively.3 In order to represent the salvation, the solvent molecules have been replaced with dielectric medium. Parameterized molecular mechanics force field (MMFF) has been used for the optimization. Refer the main manual for the detail theory of this force field. This review illustrates the full flow of docked complex optimization using MDS3.0.4



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