The present art of drug discovery and design of new drugs is based on suicidal\nirreversible inhibitors. Covalent inhibition is the strategy that is used to achieve irreversible\ninhibition. Irreversible inhibitors interact with their targets in a time-dependent fashion, and\nthe reaction proceeds to completion rather than to equilibrium. Covalent inhibitors possessed\nsome significant advantages over non-covalent inhibitors such as covalent warheads can\ntarget rare, non-conserved residue of a particular target protein and thus led to development\nof highly selective inhibitors, covalent inhibitors can be effective in targeting proteins with\nshallow binding cleavage which will led to development of novel inhibitors with increased\npotency than non-covalent inhibitors. Several computational approaches have been\ndeveloped to simulate covalent interactions; however, this is still a challenging area to\nexplore. Covalent molecular docking has been recently implemented in the computer-aided\ndrug design workflows to describe covalent interactions between inhibitors and biological\ntargets. In this review we highlight: (i) covalent interactions in biomolecular systems;\n(ii) the mathematical framework of covalent molecular docking; (iii) implementation of\ncovalent docking protocol in drug design workflows; (iv) applications covalent docking:\ncase studies and (v) shortcomings and future perspectives of covalent docking. To the best\nof our knowledge; this review is the first account that highlights different aspects of covalent\ndocking with its merits and pitfalls. We believe that the method and applications highlighted\nin this study will help future efforts towards the design of irreversible inhibitors.
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