Covalent Inhibition in Drug Discovery

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 coval...

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Bibliographic Details
Published in:ChemMedChem 2019-05, Vol.14 (9), p.889-906
Main Authors: Ghosh, Avick Kumar, Samanta, Indranil, Mondal, Anushree, Liu, Wenshe Ray
Format: Article
Language:English
Subjects:
acetylcholinesterase
caspase
cathepsin
Covalence
covalent inhibitors
Drug Discovery
Enzymes
Humans
Inclination
Industrial development
Inhibition
Inhibitors
Kinases
Medical treatment
Pharmaceutical industry
Protein kinase
protein kinases
Proteins
RAS proteins
Regulatory agencies
United States
United States Food and Drug Administration
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Summary: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. For more than 100 years there has been a general reluctance toward covalent inhibitors, given safety concern. However, thanks to modern drug discovery approaches, the development of covalent inhibitors has been flourishing in the past decade. This review summarizes the history of covalent inhibitors and recent progress in their development.
ISSN:1860-7179
1860-7187
DOI:10.1002/cmdc.201900107