The expanding repertoire of covalent warheads for drug discovery

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.

Automated summary

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.