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

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 decre...

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Bibliographic Details
Published in:ChemMedChem 2018-12, Vol.13 (23), p.2514-2521
Main Authors: Vance, Nicholas R., Witkin, Katie R., Rooney, Patrick W., Li, Yalan, Pope, Marshall, Spies, M. Ashley
Format: Article
Language:English
Subjects:
Amides
Amino Acid Isomerases - antagonists & inhibitors
Amino Acid Isomerases - metabolism
Anti-Bacterial Agents - chemistry
Anti-Bacterial Agents - pharmacology
Antibiotics
Antiinfectives and antibacterials
Antimicrobial agents
Bacillus subtilis - drug effects
Bacillus subtilis - enzymology
Bacteria - drug effects
Bacteria - enzymology
Bacterial Infections - drug therapy
Bacterial Infections - microbiology
Biosynthesis
Catalysis
Cell walls
computational chemistry
Conjugates
Covalence
Drug Discovery
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Enzyme kinetics
enzymes
Glutamate racemase
Humans
Inhibitors
Kinetics
Liabilities
Mass spectrometry
Mass spectroscopy
Methicillin
Molecular Docking Simulation
Molecular dynamics
Organic chemistry
Quantum mechanics
Reaction kinetics
Small Molecule Libraries - chemistry
Small Molecule Libraries - pharmacology
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Summary: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. Crippling the cysteine: Through structure‐based virtual screening, we present a series of covalent inhibitors of glutamate racemase, an antimicrobial drug target. Using experimental and computational techniques, we provide a chemical rationale for the conjugate addition of a small‐molecule inhibitor with a catalytic cysteine of glutamate racemase. Additionally, each compound was tested against a panel of opportunistic pathogens to determine their antimicrobial potency.
ISSN:1860-7179
1860-7187
DOI:10.1002/cmdc.201800592