One of our greatest challenges in drug design is targeting cryptic allosteric pockets in enzyme targets. Drug leads that do bind to these cryptic pockets are often discovered during HTS campaigns, and the mechanisms of action are rarely understood. Nevertheless, it is often the case that the allosteric pocket provides the best option for drug development against a given target. In the current studies we present a successful way forward in rationally exploiting the cryptic allosteric pocket of H. pylori glutamate racemase, an essential enzyme in this pathogen’s life cycle. A wide range of computational and experimental methods are employed in a workflow leading to the discovery of a series of natural product allosteric inhibitors which occupy the allosteric pocket of this essential racemase. The confluence of these studies reveals a fascinating source of the allosteric inhibition, which centers on the abolition of essential monomer-monomer coupled motion networks.
Caspase‐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).
Mapping the constellation of structural and dynamic changes concurrent with allosteric inhibitor binding to caspase‐7, also known as allosteric structure–activity relationships (ASARs), reveals the nexus between the active site and the remote allosteric pocket. These ASARs also elucidate the link between structure and catalytic power for caspase‐7. Our insights from exploration of caspase‐7 allostery offer a new path for navigating allosteric drug discovery. More information can be found in the Research Article by M. A. Spies and co‐workers (DOI: 10.1002/chem.202300872).
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