Decrypting a cryptic allosteric pocket in H. pylori glutamate racemase.
Commun Chem
; 4(1): 172, 2021 Dec 10.
Article
in En
| MEDLINE
| ID: mdl-36697800
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Language:
En
Journal:
Commun Chem
Year:
2021
Document type:
Article
Affiliation country:
United States