Allosteric Tuning of Caspase‐7: A Fragment‐Based Drug Discovery Approach

Abstract

The caspase family of cysteine proteases are highly sought-after drug targets owing to their essential roles in apoptosis,p roliferation, and inflammation pathways. Highthroughput screening efforts to discover inhibitors have gained little traction. Fragment-based screening has emerged as ap owerfula pproach for the discovery of innovative drug leads.T his method has become ac entral facet of drug discovery campaigns in the pharmaceutical industry and academia. Afragment-based drug discovery campaign against human caspase-7 resulted in the discovery of anovel series of allosteric inhibitors.A nX -ray crystal structure of caspase-7 bound to af ragment hit and at horough kinetic characterization of az ymogenic form of the enzyme were used to investigate the allosteric mechanism of inhibition. This work further advances our understanding of the mechanisms of allosteric control of this class of pharmaceutically relevant enzymes,and provides anew path forwardfor drug discovery efforts.

Determination of the binding mechanism of histone deacetylase inhibitors

“…Transient binding pockets are generally hard to predict and, as a matter of fact, have always been discovered in retrospect in structures of protein–ligand complexes as fortunate coincidence. Prominent examples for the retrospective discovery of transient binding pockets are caspase 7 (Vance, Gakhar, & Spies, ), γ‐secretase (Kukar et al., ), diverse protein kinases (Liu et al., ; Wylie et al., ; Zhang et al., ), and also histone deacetylases (Bottomley et al., ; Burli et al., ; Hudson et al., ; KrennHrubec et al., ; Rumpf et al., ).…”