Abstract
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.
Highlights
One of our greatest challenges in drug design is targeting cryptic allosteric pockets in enzyme targets
MD and QM/MM studies in Witkin et al, found that H. pylori glutamate racemase (GR) goes through a large conformational change that facilitates the acidification of the substrate Cα-proton via a protonation of the α-carboxylate oxygen from the catalytic Cys[185]; the entire process is a key part of a pre-activation step that occurs before the racemization catalytic cycle (Supplementary Fig. 1)[15]
In this study we report an MD/Docking workflow which is stress tested via the Receiver Operator Characteristic (ROC) statistical method, and results in the successful discovery of a new allosteric inhibitor of H. pylori GR, but with a completely different chemical space than Compound A, proving that the workflow presented is able to address the challenges presented by cryptic allosteric pockets
Summary
One of our greatest challenges in drug design is targeting cryptic allosteric pockets in enzyme targets. 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. In this study we report an MD/Docking workflow which is stress tested via the Receiver Operator Characteristic (ROC) statistical method, and results in the successful discovery of a new allosteric inhibitor of H. pylori GR, but with a completely different chemical space than Compound A, proving that the workflow presented is able to address the challenges presented by cryptic allosteric pockets. These findings constitute a definitive and novel type of Allosteric Structure Activity Relationship (ASAR)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
