Elucidating the Catalytic Power of Glutamate Racemase by Investigating a Series of Covalent Inhibitors.

ABSTRACT: The application of covalent inhibitors has experienced a renaissance within drug discovery programs in the last decade. To leverage the superior potency and drug target residence time of covalent inhibitors, there have been extensive efforts to develop highly specific covalent modifications to decrease off-target liabilities. Herein, we present a series of covalent inhibitors of an antimicrobial drug target, glutamate racemase, discovered through structure-based virtual screening. A combination of enzyme kinetics, mass spectrometry, and surface-plasmon resonance experiments details a highly specific 1,4-conjugate addition of a small-molecule inhibitor with a catalytic cysteine of glutamate racemase. Molecular dynamics simulations and quantum mechanics-molecular mechanics geometry optimizat

SUBMITTER: Vance NR 

PROVIDER: S-EPMC6581216 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature