Journal
DRUG DISCOVERY TODAY
Volume 28, Issue 12, Pages -Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.drudis.2023.103799
Keywords
covalent drug design; electrophilic warhead; targeted covalent inhibitors; irreversible inhibitors; covalent reversible inhibitors; chemical probes
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Covalent warheads, previously neglected for safety concerns, have gained attention due to their advantages over noncovalent drugs. The approval of several covalent inhibitors in the past decade has accelerated research in this area. Strategies are being developed to improve the potency and mitigate toxicity of covalent warheads.
The reactive functionalities of drugs that engage in covalent interactions with the enzyme/receptor residue in either a reversible or an irreversible manner are called 'warheads'. Covalent warheads that were previously neglected because of safety concerns have recently gained center stage as a result of their various advantages over noncovalent drugs, including increased selectivity, increased residence time, and higher potency. With the approval of several covalent inhibitors over the past decade, research in this area has accelerated. Various strategies are being continuously developed to tune the characteristics of warheads to improve their potency and mitigate toxicity. Here, we review research progress in warhead discovery over the past 5 years to provide valuable insights for future drug discovery.
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