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Article

Discovery of the Novel Inhibitor Against New Delhi Metallo-β-Lactamase Based on Virtual Screening and Molecular Modelling

Department of Food Science and Engineering, College of Food Science and Engineering, Jilin University, Changchun 130062, China
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Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(10), 3567; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21103567
Received: 31 March 2020 / Revised: 7 May 2020 / Accepted: 7 May 2020 / Published: 18 May 2020
(This article belongs to the Collection Computational Studies of Biomolecules)
New Delhi metallo-β-lactamase (NDM-1), one of the metallo-β-lactamases (MBLs), leads to antibiotic resistance in clinical treatments due to the strong ability of hydrolysis to almost all kinds of β-lactam antibiotics. Therefore, there is the urgent need for the research and development of the novel drug-resistant inhibitors targeting NDM-1. In this study, ZINC05683641 was screened as potential NDM-1 inhibitor by virtual screening and the inhibitor mechanism of this compound was explored based on molecular dynamics simulation. The nitrocefin assay showed that the IC50 value of ZINC05683641 was 13.59 ± 0.52 μM, indicating that the hydrolytic activity of NDM-1 can be obviously suppressed by ZINC05683641. Further, the binding mode of ZINC05683641 with NDM-1 was obtained by molecular modeling, binding free energy calculation, mutagenesis assays and fluorescence-quenching assays. As results, ILE-35, MET-67, VAL-73, TRP-93, CYS-208, ASN-220 and HIS-250 played the key roles in the binding of NDM-1 with ZINC05683641. Interestingly, these key residues were exactly located in the catalytic activity region of NDM-1, implying that the inhibitor mechanism of ZINC05683641 against NDM-1 was the competitive inhibition. These findings will provide an available approach to research and develop new drug against NDM-1 and treatment for bacterial resistance. View Full-Text
Keywords: NDM-1; drug-resistant inhibitor; molecular dynamics simulation; virtual screening NDM-1; drug-resistant inhibitor; molecular dynamics simulation; virtual screening
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MDPI and ACS Style

Wang, X.; Yang, Y.; Gao, Y.; Niu, X. Discovery of the Novel Inhibitor Against New Delhi Metallo-β-Lactamase Based on Virtual Screening and Molecular Modelling. Int. J. Mol. Sci. 2020, 21, 3567. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21103567

AMA Style

Wang X, Yang Y, Gao Y, Niu X. Discovery of the Novel Inhibitor Against New Delhi Metallo-β-Lactamase Based on Virtual Screening and Molecular Modelling. International Journal of Molecular Sciences. 2020; 21(10):3567. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21103567

Chicago/Turabian Style

Wang, Xiyan, Yanan Yang, Yawen Gao, and Xiaodi Niu. 2020. "Discovery of the Novel Inhibitor Against New Delhi Metallo-β-Lactamase Based on Virtual Screening and Molecular Modelling" International Journal of Molecular Sciences 21, no. 10: 3567. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21103567

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