The DOI matches its Crossref record; 96 of the 97 references it cites were found in a registry or an index.
Covalent inhibitors in drug discovery: from accidental discoveries to avoided liabilities and designed therapies
Abstract
Drugs that covalently bond to their biological targets have a long history in drug discovery. A look at drug approvals in recent years suggests that covalent drugs will continue to make impacts on human health for years to come. Although fraught with concerns about toxicity, the high potencies and prolonged effects achievable with covalent drugs may result in less-frequent drug dosing and in wide therapeutic margins for patients. Covalent inhibition can also dissociate drug pharmacodynamics (PD) from pharmacokinetics (PK), which can result in desired drug efficacy for inhibitors that have short systemic exposure. Evidence suggests that there is a reduced risk for the development of resistance against covalent drugs, which is a major challenge in areas such as oncology and infectious disease.
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“Hence, covalent inhibitors have the advantage of sustained inhibition and a longer residence time compared to non-covalent inhibitors because the covalently bound target is continuously inhibited until protein degradation and regeneration.28”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [28]
In the citing paper
“Covalent inhibitors, also known as irreversible inhibitors, are a class of inhibitors that bind to amino acid residues of target proteins through covalent bonds formed by mildly reactive functional groups to confer additional affinity, compared to that of non-covalent inhibitors, which achieve binding and inhibition of target proteins through non-covalent interactions such as hydrogen bond and van”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [28]
Citations
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1 of the 97 references couldn’t be matched to a known paper.
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Oridonin is a covalent NLRP3 inhibitor with strong anti-inflammasome activity
He, H., Jiang, H., Chen, Y., Ye, J., Wang, A., Wang, C., Liu, Q., Liang, G., Deng, X., Jiang, W., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-04947-6 · Cited by 827
Gehringer, M., & Laufer, S. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b01153 · Cited by 772
Jackson, P. A., Widen, J. C., Harki, D. A., & Brummond, K. M. (2017) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6b00788 · Cited by 588
Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease
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Ertl, P., Altmann, E., & McKenna, J. M. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c00754 · Cited by 448
Metadata
- Authors
- Bauer, R. A.
- Affiliations
- Eli Lilly (United States) (US)
- Corresponding author
- Bauer, Renato A.
- ORCID
- Bauer, Renato A.
- Venue
- Drug Discovery Today
- Publisher
- Elsevier BV
- Published
- 2015-09
- Volume
- 20
- Issue
- 9
- Pages
- 1061-1073
- ISSN
- 1359-6446 (ISSN-L)
- OpenAlex
- W248383993
- Cited by
- 534
- References
- 97
- Citations by year
- 2026: 36 · 2025: 43 · 2024: 46 · 2023: 56 · 2022: 57 · 2021: 70 · 2020: 57 · 2019: 51 · 2018: 47 · 2017: 33 · 2016: 29 · 2015: 8
- FWCI
- 1.90
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Drug Discovery Today (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Physical Sciences › Chemistry › Organic Chemistry › Click Chemistry and Applications
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › Computational Drug Discovery Methods
- Keywords
- covalent inhibitors, covalent drug design, history of drug discovery, drug toxicity, drug resistance, oncology therapeutics, infectious disease therapeutics, therapeutic window
- MeSH terms
- Drug Resistance, Pharmaceutical Preparations, Humans, Pharmacokinetics, Drug Design, Drug Approval, Drug Discovery, Molecular Targeted Therapy
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