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Cited by 265Click Chemistry and ApplicationsProtein Degradation and InhibitorsProtein Kinase Regulation and GTPase Signaling

Covalent Inhibition in Drug Discovery

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Ghosh, Avick Kumar, Samanta, Indranil, Mondal, Anushree, Liu, Wenshe Ray·2019·ChemMedChem
DOI 10.1002/cmdc.201900107PMC PMC6816337
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Abstract

Although covalent inhibitors have been used as therapeutics for more than a century, there has been general resistance in the pharmaceutical industry against their further development due to safety concerns. This inclination has recently been reverted after the development of a wide variety of covalent inhibitors to address human health conditions along with the US Food and Drug Administration (FDA) approval of several covalent therapeutics for use in humans. Along with this exciting resurrection of an old drug discovery concept, this review surveys enzymes that can be targeted by covalent inhibitors for the treatment of human diseases. We focus on protein kinases, RAS proteins, and a few other enzymes that have been studied extensively as targets for covalent inhibition, with the aim to address challenges in designing effective covalent drugs and to provide suggestions in the area that have yet to be explored.

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  • Concerns about assay interference and poor selectivity historically discouraged investigation of reactive molecules.

    “Historically, concerns about the interference of these reactive molecules with biological assays and potential lack of selectivity often discouraged further investigation2,3.”

    From Advances in covalent drug discovery (2022) · cites this paper as [3]

  • Nirmatrelvir covalently inhibits SARS-CoV-2 main protease.

    “Nirmatrelvir (Table 1) covalently inhibits the Mpro of SARS-CoV-2 (ref.3).”

    From Advances in covalent drug discovery (2022) · cites this paper as [3]

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Authors
Ghosh, A. K., Samanta, I., Mondal, A., & Liu, W. R.
Affiliations
Texas A&M University (US)
Corresponding author
Liu, Wenshe Ray
ORCID
Venue
ChemMedChem
Publisher
Wiley
Published
2019-03-26
Volume
14
Issue
9
Pages
889-906
ISSN
  • 1860-7179 (ISSN-L)
  • 1860-7187
DOI
10.1002/cmdc.201900107
PMC
PMC6816337
OpenAlex
W2918370785
Cited by
265
References
170
Citations by year
2026: 28 · 2025: 28 · 2024: 30 · 2023: 36 · 2022: 47 · 2021: 53 · 2020: 37 · 2019: 6
FWCI
2.82
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • ChemMedChem (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institute of General Medical Sciences (R01GM121584)
  • Cancer Prevention and Research Institute of Texas (RP170797)
  • Welch Foundation (A-1715)
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 › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords
covalent inhibitors, covalent drug design, protein kinases, Ras proteins, enzyme inhibitors, drug safety, drug discovery
MeSH terms
Humans, United States, United States Food and Drug Administration, Drug Discovery

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