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Covalent inhibitors design and discovery.

De Cesco, Stephane, Kurian, Jerry, Dufresne, Caroline, Mittermaier, Anthony K., Moitessier, Nicolas·2017·European Journal of Medicinal Chemistry

DOI 10.1016/j.ejmech.2017.06.019

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Abstract

In the history of therapeutics, covalent drugs occupy a very distinct category. While representing a significant fraction of the drugs on the market, very few have been deliberately designed to interact covalently with their biological target. In this review, the prevalence of covalent drugs will first be briefly covered, followed by an introduction to their mechanisms of action and more detailed discussions of their discovery and the development of safe and efficient covalent enzyme inhibitors. All stages of a drug discovery program will be covered, from target considerations to lead optimization, strategies to tune reactivity and computational methods. The goal of this article is to provide an overview of the field and to outline good practices that are needed for the proper assessment and development of covalent inhibitors as well as a good understanding of the potential and limitations of current computational methods for the design of covalent drugs.

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Authors: De Cesco, S., Kurian, J., Dufresne, C., Mittermaier, A. K., & Moitessier, N.
Affiliations: McGill University (CA)
Corresponding author: Moitessier, Nicolas
ORCID: Mittermaier, Anthony K.
Moitessier, Nicolas
Venue: European Journal of Medicinal Chemistry
Publisher: Elsevier BV
Published: 2017-09
Volume: 138
Pages: 96-114
ISSN: 0223-5234 (ISSN-L)
DOI: 10.1016/j.ejmech.2017.06.019
OpenAlex: W2622009965
Cited by: 315
References: 127
Citations by year: 2026: 20 · 2025: 41 · 2024: 30 · 2023: 39 · 2022: 30 · 2021: 46 · 2020: 45 · 2019: 30 · 2018: 28 · 2017: 5
FWCI: 1.76
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: European Journal of Medicinal Chemistry (publishedVersion)
PubMed (publishedVersion)
Funders: CIHR (MOP-136943)
Topics: Physical Sciences › Chemistry › Organic Chemistry › Click Chemistry and Applications
Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › Computational Drug Discovery Methods
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Enzyme function and inhibition
Keywords: covalent inhibitors, covalent enzyme inhibitors, drug discovery, lead optimization, reactivity tuning, computer-aided drug design, mechanism of action, target selection, drug safety
MeSH terms: Biological Products, Humans, Kinetics, Quantum Theory, Drug Discovery

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