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Covalent inhibitors design and discovery.
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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“However, there is a whole class of inhibitors that form a covalent bond with their enzyme/receptor target (De Cesco et al., 2017).”
From Empirical scoring functions for structure-based virtual screening: applications, critical aspects, and challenges (2018) · cites this paper as De Cesco et al., 2017
In the citing paper
“Two critical aspects in the future development of covalent scoring functions are the capacity to predict the kinetics of ligand binding (e.g., residence times) and the intrinsic reactivity of electrophilic and nucleophilic pairs of atoms (De Cesco et al., 2017).”
From Empirical scoring functions for structure-based virtual screening: applications, critical aspects, and challenges (2018) · cites this paper as De Cesco et al., 2017
In the citing paper
“The development of covalent-docking methodologies capable of dealing with such type of inhibition is very important due to the potential advantages associated with covalent inhibitors (De Cesco et al., 2017), including (i) sustained duration of action leading to less frequent dosing, (ii) increased ligand efficiency, (iii) ability to inhibit targets with shallow binding sites previously”
From Empirical scoring functions for structure-based virtual screening: applications, critical aspects, and challenges (2018) · cites this paper as De Cesco et al., 2017
In the citing paper
“Due to the increasing interest in covalent drugs, many non-covalent docking programs have developed covalent versions and some new docking programs focused on covalent ligands have been developed (Kumalo et al., 2015; Awoonor-Williams et al., 2017; De Cesco et al., 2017).”
From Empirical scoring functions for structure-based virtual screening: applications, critical aspects, and challenges (2018) · cites this paper as De Cesco et al., 2017
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Metadata
- Authors
- De Cesco, S., Kurian, J., Dufresne, C., Mittermaier, A. K., & Moitessier, N.
- Affiliations
- McGill University (CA)
- Corresponding author
- Moitessier, Nicolas
- Venue
- European Journal of Medicinal Chemistry
- Publisher
- Elsevier BV
- Published
- 2017-09
- Volume
- 138
- Pages
- 96-114
- ISSN
- 0223-5234 (ISSN-L)
- 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
- 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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