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Covalent inhibitors in drug discovery: from accidental discoveries to avoided liabilities and designed therapies

Bauer, Renato A.·2015·Drug Discovery Today

DOI 10.1016/j.drudis.2015.05.005

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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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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)
DOI: 10.1016/j.drudis.2015.05.005
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
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
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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Covalent inhibitors in drug discovery: from accidental discoveries to avoided liabilities and designed therapies

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