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

Nicholas R Vance; Katie R Witkin; Patrick W Rooney; Yalan Li; Marshall Pope; M Ashley Spies

doi:10.1002/cmdc.201800592

Back

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

Journal article

Open access

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

Nicholas R Vance, Katie R Witkin, Patrick W Rooney, Yalan Li, Marshall Pope and M Ashley Spies

ChemMedChem, Vol.13(23), pp.2514-2521

12/06/2018

DOI: 10.1002/cmdc.201800592

PMCID: PMC6581216

PMID: 30264520

Files and links (1)

url

https://www.ncbi.nlm.nih.gov/pmc/articles/6581216View

Open Access

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 optimizations reveal the chemistry of the conjugate addition. Two compounds from this series of inhibitors display antimicrobial potency similar to β-lactam antibiotics, with significant activity against methicillin-resistant S. aureus strains. This study elucidates a detailed chemical rationale for covalent inhibition and provides a platform for the development of antimicrobials with a novel mechanism of action against a target in the cell wall biosynthesis pathway.

Amino Acid Isomerases - antagonists & inhibitors

Amino Acid Isomerases - metabolism

Anti-Bacterial Agents - chemistry

Anti-Bacterial Agents - pharmacology

Bacillus subtilis - drug effects

Bacillus subtilis - enzymology

Bacteria - drug effects

Bacteria - enzymology

Bacterial Infections - drug therapy

Bacterial Infections - microbiology

Drug Discovery

Enzyme Inhibitors - chemistry

Enzyme Inhibitors - pharmacology

Humans

Molecular Docking Simulation

Small Molecule Libraries - chemistry

Small Molecule Libraries - pharmacology

Details

Title: Subtitle: Elucidating the Catalytic Power of Glutamate Racemase by Investigating a Series of Covalent Inhibitors
Creators: Nicholas R Vance - University of Iowa
Katie R Witkin - University of Iowa
Patrick W Rooney - University of Iowa
Yalan Li - University of Iowa
Marshall Pope - Roy J. and Lucille A. Carver College of Medicine
M Ashley Spies - University of Iowa
Resource Type: Journal article
Publication Details: ChemMedChem, Vol.13(23), pp.2514-2521
DOI: 10.1002/cmdc.201800592
PMID: 30264520
PMCID: PMC6581216
NLM abbreviation: ChemMedChem
ISSN: 1860-7179
eISSN: 1860-7187
Grant note: R01 GM097373 / NIGMS NIH HHS T32 GM008365 / NIGMS NIH HHS
Language: English
Date published: 12/06/2018
Academic Unit: Pharmaceutical Sciences and Experimental Therapeutics; Orthopedics and Rehabilitation; Biochemistry and Molecular Biology; Medicine Administration; Medicinal and Natural Products Chemistry
Record Identifier: 9984293082902771

Metrics

9 Record Views

5 Times Cited - Web of Science