期刊
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
卷 431, 期 1, 页码 2-7出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2012.12.141
关键词
New Delhi metallo-beta-lactmase-1; Metallo-beta-lactamase; Molecular dynamics simulations; Molecular mechanics/Poisson-Boltzmann surface area
资金
- National High Technology Research and Development Program of China [2012AA020302, 2012AA020301]
- National Natural Science Foundation of China [21021063, 81230076, 21210003, 21073034]
- Key Project of Chinese National Programs for Fundamental Research and Development [2009CB918502]
- Natural Science Foundation of the Fujian Province [2010J05023]
- National Science and Technology Major Project Key New Drug Creation and Manufacturing Program [2013ZX09507-004]
New Delhi metallo-beta-lactmase-1 (NDM-1) is an enzyme that confers antibiotic resistance to bacteria and is thus a serious threat to human health. Almost all clinically available beta-lactam antibiotics can be hydrolyzed by NDM-1. To determine the mechanism behind the wide substrate diversity and strong catalytic ability of NDM-1, we explored the molecular interactions between NDM-1 and different beta-lactam antibiotics using computational methods. Molecular dynamics simulations and binding free energy calculations were performed on enzyme-substrate (ES) complex models of NDM-1-Meropenem, NDM-1-Nitrocefin, and NDM-1-Ampicillin constructed by molecular docking. Our computational results suggest that mutant residues Ile35 and Lys216, and active site loop L1 residues 65-73 in NDM-1 play crucial roles in substrate recognition and binding. The results of our study provide new insights into the mechanism behind the enhanced substrate binding and wider substrate spectrum of NDM-1 compared with its homologous enzymes CcrA and IMP-1. These insights may be useful in the discovery and design of specific and potent inhibitors against NDM-1. (C) 2013 Elsevier Inc. All rights reserved.
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