Mechanism-based inhibition of zinc-dependent histone deacetylases

The hallmark of a mechanism-based inhibitor is a chemical transformation that occurs upon binding in an enzyme active site that typically yields a more potent inhibitory species. A mechanism-based enzyme inhibitor can be a closely-related analogue of the native substrate, or it can be strikingly different in its structure. Here, the discovery of mechanism-based inhibitors is briefly reviewed to establish a foundation for understanding the mechanism-based inhibition of zinc-dependent histone deacetylases (HDACs), enzymes that play critical roles in epigenetics and the regulation of myriad cellular processes. Notably, the discovery of mechanism-based HDAC inhibition was an unexpected surprise emanating from X-ray crystal structures of enzyme-inhibitor complexes. In each example discussed, the C[double bond, length as m-dash]O, C[double bond, length as m-dash]N, or C[triple bond, length as m-dash]N group of an inhibitor undergoes nucleophilic attack by zinc-bound water in the same manner as the C[double bond, length as m-dash]O group of the native HDAC substrate; however, nucleophilic attack at the bound inhibitor leads to the formation of a tightly-bound enzyme-inhibitor complex. The dual requirements of steric fit as well as fitness for chemical activation can be exploited in unique strategies to enhance inhibitory potency and selectivity.