Affiliation:
1. Biochemistry and Molecular Biology Department University of Iowa 51 Newton Road, 4-403 Bowen Science Building Iowa City IA 52242 USA
2. Pharmaceutics and Experimental Therapeutics Department Medicinal and Natural Products Chemistry Division University of Iowa 180 South Grand Avenue Iowa City IA 52242 USA
Abstract
AbstractCaspase‐7 (C7), a cysteine protease involved in apoptosis, is a valuable drug target for its role in human diseases (e. g., Parkinson's, Alzheimer's, sepsis). The C7 allosteric site has great potential for small‐molecule targeting, but numerous drug discovery efforts have identified precious few allosteric inhibitors. Here we present the first selective, drug‐like inhibitor of C7 along with several other improved inhibitors based on our previous fragment hit. We also provide a rational basis for the impact of allosteric binding on the C7 catalytic cycle by using an integrated approach including X‐ray crystallography, stopped‐flow kinetics, and molecular dynamics simulations. Our findings suggest allosteric binding disrupts C7 pre‐acylation by neutralization of the catalytic dyad, displacement of substrate from the oxyanion hole, and altered dynamics of substrate binding loops. This work advances drug targeting efforts and bolsters our understanding of allosteric structure–activity relationships (ASARs).
Funder
National Institute of General Medical Sciences
Subject
General Chemistry,Catalysis,Organic Chemistry