Navigating P450 recognition: Selectivity, inhibition, and substrate mimicry

Cytochrome P450 (CYP450) are highly versatile enzymes found across all kingdoms of life. Despite low sequence similarity, they share a conserved triangular prism fold and a heme cofactor. They are renowned for their exceptional regio- and stereoselectivity, coupled with active-site plasticity that enables them to process an unmatched range of substrates—from small alkanes to drugs and cyclic peptides—across a wide range of molecular weights and physicochemical properties. This review focuses on the structural features that govern substrate recognition, with particular emphasis on how researchers leverage these features to engineer new substrate selectivity and activity through anchoring groups or decoy molecules. The second part discusses the design of selective inhibitors for human P450 enzymes, especially CYP3A4, CYP17A1 and CYP19A1.