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

Autor: Vance NR; Division of Medicinal and Natural Products Chemistry, College of Pharmacy, University of Iowa, 115 S. Grand Ave., Iowa City, IA, 52242, USA., Witkin KR; Division of Medicinal and Natural Products Chemistry, College of Pharmacy, University of Iowa, 115 S. Grand Ave., Iowa City, IA, 52242, USA., Rooney PW; Department of Biochemistry, Carver College of Medicine, University of Iowa, 51 Newton Road, 4-403 Bowen Science Building, Iowa City, IA, 52242, USA., Li Y; Proteomics Facility, Carver College of Medicine, University of Iowa, 355 EMRB, Iowa City, IA, 52242, USA., Pope M; Proteomics Facility, Carver College of Medicine, University of Iowa, 355 EMRB, Iowa City, IA, 52242, USA., Spies MA; Division of Medicinal and Natural Products Chemistry, College of Pharmacy, University of Iowa, 115 S. Grand Ave., Iowa City, IA, 52242, USA.; Department of Biochemistry, Carver College of Medicine, University of Iowa, 51 Newton Road, 4-403 Bowen Science Building, Iowa City, IA, 52242, USA.
Jazyk: angličtina
Zdroj: ChemMedChem [ChemMedChem] 2018 Dec 06; Vol. 13 (23), pp. 2514-2521. Date of Electronic Publication: 2018 Nov 21.
DOI: 10.1002/cmdc.201800592
Abstrakt: 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.
(© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)
Databáze: MEDLINE
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