Covalent inhibitors: an opportunity for rational target selectivity
Open accessAbstract
There is a resurging interest in compounds that engage their target through covalent interactions. Cysteine's thiol is endowed with enhanced reactivity, making it the nucleophile of choice for covalent engagement with a ligand aligning an electrophilic trap with a cysteine residue in a target of interest. The paucity of cysteine in the proteome coupled to the fact that closely related proteins do not necessarily share a given cysteine residue enable a level of unprecedented rational target selectivity. The recent demonstration that a lysine's amine can also be engaged covalently with a mild electrophile extends the potential of covalent inhibitors. The growing database of protein structures facilitates the discovery of covalent inhibitors while the advent of proteomic technologies enables a finer resolution in the selectivity of covalently engaged proteins. Here, we discuss recent examples of discovery and design of covalent inhibitors.
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Covalent ligand screening from electrophilic compound libraries is becoming more common.
“Covalent ligand screening is another ligand discovery approach that is becoming more common, whereby various methods are used to discover covalent ligands from libraries of electrophilic compounds7,12,13.”
From Advances in covalent drug discovery (2022) · cites this paper as [12]
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- Authors
- Lagoutte, R., Patouret, R., & Winssinger, N.
- Affiliations
- University of Geneva (CH)
- Corresponding author
- Winssinger, Nicolas
- ORCID
- Winssinger, Nicolas
- Venue
- Current Opinion in Chemical Biology
- Publisher
- Elsevier BV
- Published
- 2017-08
- Volume
- 39
- Pages
- 54-63
- ISSN
- 1367-5931 (ISSN-L)
- OpenAlex
- W2623565822
- Cited by
- 138
- References
- 49
- Citations by year
- 2026: 12 · 2025: 11 · 2024: 10 · 2023: 17 · 2022: 16 · 2021: 20 · 2020: 21 · 2019: 10 · 2018: 18 · 2017: 2
- FWCI
- 0.83
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (am, 313 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Current Opinion in Chemical Biology (acceptedVersion)
- PubMed (publishedVersion)
- Archive ouverte UNIGE (University of Geneva) (acceptedVersion, other-oa)
- Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
- Funders
- NCCR Chemical Biology
- Swiss National Science Foundation
- ERC
- Topics
- Physical Sciences › Chemistry › Organic Chemistry › Click Chemistry and Applications
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Keywords
- covalent inhibitors, cysteine thiols, structure-based drug design, inhibitor discovery
- MeSH terms
- Amino Acid Sequence, Animals, Biological Products, Enzyme Inhibitors, Humans, Drug Discovery
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