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Theory and Applications of Covalent Docking in Drug Discovery: Merits and Pitfalls

Molecular Modelling and Drug Design Research Group, School of Health Sciences, University of KwaZulu-Natal, Westville, Durban 4000, South Africa
Author to whom correspondence should be addressed.
Academic Editor: Rino Ragno
Molecules 2015, 20(2), 1984-2000;
Received: 12 November 2014 / Revised: 19 December 2014 / Accepted: 12 January 2015 / Published: 27 January 2015
(This article belongs to the Special Issue Molecular Docking in Drug Design)
PDF [1935 KB, uploaded 27 January 2015]


he 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. View Full-Text
Keywords: covalent docking; covalent inhibition; covalent interactions; irreversible inhibition covalent docking; covalent inhibition; covalent interactions; irreversible inhibition

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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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MDPI and ACS Style

Kumalo, H.M.; Bhakat, S.; Soliman, M.E.S. Theory and Applications of Covalent Docking in Drug Discovery: Merits and Pitfalls. Molecules 2015, 20, 1984-2000.

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