title: Structure-based computational study of the hydrolysis of New Delhi metallo-β-lactmase-1.
abstract: New Delhi metallo-β-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 β-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 β-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.
authors: Department of Chemistry, Fuzhou University, Fujian 350108, China.
authors: Kongkai
authors: K
authors: Zhu
authors: Junyan
authors: J
authors: Lu
authors: Fei
authors: F
authors: Ye
authors: Lu
authors: L
authors: Jin
authors: Xiangqian
authors: X
authors: Kong
authors: Zhongjie
authors: Z
authors: Liang
authors: Yong
authors: Y
authors: Chen
authors: Kunqian
authors: K
authors: Yu
authors: Hualiang
authors: H
authors: Jiang
authors: Jun-Qian
authors: JQ
authors: Li
authors: Cheng
authors: C
authors: Luo
mesh_terms: D000667:Ampicillin / Q000737:chemistry; D002384:Catalysis; D002511:Cephalosporins / Q000737:chemistry; D006860:Hydrogen Bonding; D006868:Hydrolysis; D000077731:Meropenem; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D017433:Protein Structure, Secondary; D013379:Substrate Specificity; D013845:Thienamycins / Q000737:chemistry; D001618:beta-Lactamases / Q000737:chemistry*
chemical_list: D002511:Cephalosporins; D013845:Thienamycins; D000667:Ampicillin; D001618:beta-Lactamases; C552864:beta-lactamase NDM-1; C021720:nitrocefin; D000077731:Meropenem