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

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 c...

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Autores principales: Kumalo, Hezekiel Mathambo, Bhakat, Soumendranath, Soliman, Mahmoud E. S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6272664/
https://www.ncbi.nlm.nih.gov/pubmed/25633330
http://dx.doi.org/10.3390/molecules20021984
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author Kumalo, Hezekiel Mathambo
Bhakat, Soumendranath
Soliman, Mahmoud E. S.
author_facet Kumalo, Hezekiel Mathambo
Bhakat, Soumendranath
Soliman, Mahmoud E. S.
author_sort Kumalo, Hezekiel Mathambo
collection PubMed
description 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.
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spelling pubmed-62726642018-12-13 Theory and Applications of Covalent Docking in Drug Discovery: Merits and Pitfalls Kumalo, Hezekiel Mathambo Bhakat, Soumendranath Soliman, Mahmoud E. S. Molecules Review 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. MDPI 2015-01-27 /pmc/articles/PMC6272664/ /pubmed/25633330 http://dx.doi.org/10.3390/molecules20021984 Text en © 2015 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Kumalo, Hezekiel Mathambo
Bhakat, Soumendranath
Soliman, Mahmoud E. S.
Theory and Applications of Covalent Docking in Drug Discovery: Merits and Pitfalls
title Theory and Applications of Covalent Docking in Drug Discovery: Merits and Pitfalls
title_full Theory and Applications of Covalent Docking in Drug Discovery: Merits and Pitfalls
title_fullStr Theory and Applications of Covalent Docking in Drug Discovery: Merits and Pitfalls
title_full_unstemmed Theory and Applications of Covalent Docking in Drug Discovery: Merits and Pitfalls
title_short Theory and Applications of Covalent Docking in Drug Discovery: Merits and Pitfalls
title_sort theory and applications of covalent docking in drug discovery: merits and pitfalls
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6272664/
https://www.ncbi.nlm.nih.gov/pubmed/25633330
http://dx.doi.org/10.3390/molecules20021984
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