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Structure-based design of targeted covalent inhibitors

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Abstract

Covalent inhibition is a rapidly growing discipline within drug discovery. Many historical covalent inhibitors were discovered by serendipity, with such a mechanism of action often regarded as undesirable due to potential toxicity issues. Recent progress has seen a major shift in this outlook, as covalent inhibition shows promise for targets where previous efforts to identify non-covalent small molecule inhibitors have failed. Targeted covalent inhibitors (TCIs) can offer drug discovery scientists the ability to increase the potency and/or selectivity of small molecule inhibitors, by attachment of reactive functional groups designed to covalently bind to specific sites in a target. In this tutorial review we introduce the broader concept of covalent inhibition, discuss the potential benefits and challenges of such an approach, and provide an overview of the current status of the field. We also describe some strategies and computational tools to enable successful covalent drug discovery.

Graphical abstract: Structure-based design of targeted covalent inhibitors

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Publication details

The article was received on 07 Feb 2018 and first published on 05 Apr 2018


Article type: Tutorial Review
DOI: 10.1039/C7CS00220C
Citation: Chem. Soc. Rev., 2018, Advance Article
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    Structure-based design of targeted covalent inhibitors

    R. Lonsdale and R. A. Ward, Chem. Soc. Rev., 2018, Advance Article , DOI: 10.1039/C7CS00220C

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