Elucidation of enzyme mechanisms to design potent and selective inhibitors

The Murkin Lab’s focus is to design inhibitors of enzymes involved in disease by exploiting the enzyme’s mechanism in one of two ways:

(1) Because most enzymes have evolved to stabilize the reaction’s transition state, we establish a model of the transition state that serves as a template for synthesizing chemically stable analogues with exceptionally potent affinity.

(2) Covalent inhibitors bearing functional groups that become activated within the active site can lead to high selectivity, minimizing undesired side effects associated with intrinsic reactivity off target.