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A quantum mechanics/molecular mechanics study on the hydrolysis mechanism of New Delhi metallo-beta-lactamase-1

文献类型：期刊论文

作者Zhu, Kongkai1,3; Lu, Junyan3; Liang, Zhongjie2; Kong, Xiangqian3; Ye, Fei3; Jin, Lu3; Geng, Heji1,3; Chen, Yong1; Zheng, Mingyue3; Jiang, Hualiang3
刊名JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN
出版日期2013-03
卷号27期号:3页码:247-256
关键词QM/MM NDM-1 MD Catalytic mechanism beta-Lactam antibiotics
ISSN号0920-654X
DOI10.1007/s10822-012-9630-6
文献子类Article
英文摘要New Delhi metallo-beta-lactamase-1 (NDM-1) has emerged as a major global threat to human health for its rapid rate of dissemination and ability to make pathogenic microbes resistant to almost all known beta-lactam antibiotics. In addition, effective NDM-1 inhibitors have not been identified to date. In spite of the plethora of structural and kinetic data available, the accurate molecular characteristics of and details on the enzymatic reaction of NDM-1 hydrolyzing beta-lactam antibiotics remain incompletely understood. In this study, a combined computational approach including molecular docking, molecular dynamics simulations and quantum mechanics/molecular mechanics calculations was performed to characterize the catalytic mechanism of meropenem catalyzed by NDM-1. The quantum mechanics/molecular mechanics results indicate that the ionized D124 is beneficial to the cleavage of the C-N bond within the beta-lactam ring. Meanwhile, it is energetically favorable to form an intermediate if no water molecule coordinates to Zn2. Moreover, according to the molecular dynamics results, the conserved residue K211 plays a pivotal role in substrate binding and catalysis, which is quite consistent with previous mutagenesis data. Our study provides detailed insights into the catalytic mechanism of NDM-1 hydrolyzing meropenem beta-lactam antibiotics and offers clues for the discovery of new antibiotics against NDM-1 positive strains in clinical studies.
WOS关键词METALLO-BETA-LACTAMASE ; MOLECULAR-DYNAMICS SIMULATIONS ; AMBER FORCE-FIELD ; BACTEROIDES-FRAGILIS ; ANTIBIOTIC-RESISTANCE ; CRYSTAL-STRUCTURE ; GEOMETRY OPTIMIZATION ; ORBITAL METHOD ; ACTIVE-SITE ; RESP MODEL
资助项目National High Technology Research and Development Program of China[2012AA020302] ; National Natural Science Foundation of China[20972174] ; National Natural Science Foundation of China[91029704] ; National Natural Science Foundation of China[21073034] ; National Natural Science Foundation of China[21210003] ; National Natural Science Foundation of China[21021063] ; Key Project of Chinese National Programs for Fundamental Research and Development[2009CB918502] ; Natural Science Foundation of the Fujian Province[2010J05023] ; Guangdong ST Dept.[2010A030100006] ; Key New Drug Creation and Manufacturing Program[2013ZX09507-004]
WOS研究方向Biochemistry & Molecular Biology ; Biophysics ; Computer Science
语种英语
WOS记录号WOS:000318411400004
出版者SPRINGER
源URL[http://119.78.100.183/handle/2S10ELR8/277701]  
专题药物发现与设计中心
中科院受体结构与功能重点实验室
新药研究国家重点实验室
通讯作者Chen, Yong
作者单位1.Fuzhou Univ, Dept Chem, Fuzhou 350108, Fujian, Peoples R China;
2.Soochow Univ, Ctr Syst Biol, Suzhou 215006, Jiangsu, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China;
推荐引用方式
GB/T 7714		 Zhu, Kongkai,Lu, Junyan,Liang, Zhongjie,et al. A quantum mechanics/molecular mechanics study on the hydrolysis mechanism of New Delhi metallo-beta-lactamase-1[J]. JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN,2013,27(3):247-256.
APA Zhu, Kongkai.,Lu, Junyan.,Liang, Zhongjie.,Kong, Xiangqian.,Ye, Fei.,...&Luo, Cheng.(2013).A quantum mechanics/molecular mechanics study on the hydrolysis mechanism of New Delhi metallo-beta-lactamase-1.JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN,27(3),247-256.
MLA Zhu, Kongkai,et al."A quantum mechanics/molecular mechanics study on the hydrolysis mechanism of New Delhi metallo-beta-lactamase-1".JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN 27.3(2013):247-256.

入库方式： OAI收割

来源：上海药物研究所

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