Abstract
The present art of drug discovery and design of new drugs is based on suicidal irreversible inhibitors. Covalent inhibition is the strategy that is used to achieve irreversible inhibition. Irreversible inhibitors interact with their targets in a time-dependent fashion, and the reaction proceeds to completion rather than to equilibrium. Covalent inhibitors possessed some significant advantages over non-covalent inhibitors such as covalent warheads can target rare, non-conserved residue of a particular target protein and thus led to development of highly selective inhibitors, covalent inhibitors can be effective in targeting proteins with shallow binding cleavage which will led to development of novel inhibitors with increased potency than non-covalent inhibitors. Several computational approaches have been developed to simulate covalent interactions; however, this is still a challenging area to explore. Covalent molecular docking has been recently implemented in the computer-aided drug design workflows to describe covalent interactions between inhibitors and biological targets. In this review we highlight: (i) covalent interactions in biomolecular systems; (ii) the mathematical framework of covalent molecular docking; (iii) implementation of covalent docking protocol in drug design workflows; (iv) applications covalent docking: case studies and (v) shortcomings and future perspectives of covalent docking. To the best of our knowledge; this review is the first account that highlights different aspects of covalent docking with its merits and pitfalls. We believe that the method and applications highlighted in this study will help future efforts towards the design of irreversible inhibitors.
Highlights
Computational and molecular modeling tools have become a close counterpart to experiment in the understanding of molecular aspects of biological systems [1,2,3,4]
The computational approaches like homology modeling, molecular docking and quantitative structure activity relationships (QSAR) and molecular dynamics (MD) are widely employed to discover the novel hits for various therapeutic targets
(Section 4) we provide an up-to-date literature survey on the different computer-aided drug design approaches that utilize covalent molecular docking as a tool to describe covalent enzyme inhibition
Summary
Computational and molecular modeling tools have become a close counterpart to experiment in the understanding of molecular aspects of biological systems [1,2,3,4]. The computational approaches like homology modeling, molecular docking and quantitative structure activity relationships (QSAR) and molecular dynamics (MD) are widely employed to discover the novel hits for various therapeutic targets. We have highlighted the interface between computational approaches and experiment as crucial tools in the drug discovery machinery [5]. With the prominent rising interest towards the design of covalent inhibitors, in this review we cover different aspects of covalent molecular docking as a tool that can be applied to understand covalent interactions between inhibitors and their target proteins
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