New Electrophiles and Strategies for Mechanism-Based and Targeted Covalent Inhibitor Design.

Covalent inhibitors are experiencing a growing resurgence in drug design and are an increasingly useful tool in molecular biology. The ability to attach inhibitors to their targets by a covalent linkage offers pharmacodynamic and pharmacokinetic advantages, but this can also be a liability if undesired off-target reactions are not mitigated. The discovery of new electrophilic groups that react selectively with specific amino acid residues is therefore highly desirable in the design of targeted covalent inhibitors (TCIs). Additionally, the ability to control the reactivity through exploitation of the target enzyme's machinery, as in mechanism-based inhibitors (MBIs), greatly benefits from the discovery of new strategies. This Perspective showcases recent advances in electrophile development and their application in TCIs and MBIs, exhibiting high selectivity for their targets.