In Pursuit of Enduring Inactivation: A Perspective on the Development and Study of Irreversible-Covalent Inhibitors

Abstract Molecules that form irreversible covalent bonds with their targets are a mainstay of drug discovery and chemical biology research. Their ability to permanently inactivate an enzyme target provides a mechanism with significant potential to modulate disease phenotypes. This perspective discusses the trajectory of the field of irreversible enzyme inhibitors with an outlook on emerging methods, warhead structures, and sentiments presently directing practices in the discovery and design of the next wave of covalent agents.