Binding Interaction Analysis of the Active Site and Its Inhibitors for Neuraminidase (N1 Subtype) of Human Influenza Virus by the Integration of Molecular Docking, FMO Calculation and 3D-QSAR CoMFA Modeling
Binding Interaction Analysis of the Active Site and Its Inhibitors for Neuraminidase (N1 Subtype) of Human Influenza Virus by the Integration of Molecular Docking, FMO Calculation and 3D-QSAR CoMFA Modeling
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DOI：
10.1021/ci800041k
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发表时间：
2008-08
影响因子：
5.6
通讯作者：
Qingye Zhang;Jiaoyan Yang;Kun Liang;Lingling Feng;Sanpin Li;Jian Wan;Xin Xu;Guangfu Yang;
中科院分区：
文献类型：
--
作者：
Qingye Zhang;Jiaoyan Yang;Kun Liang;Lingling Feng;Sanpin Li;Jian Wan;Xin Xu;Guangfu Yang;
近期，高毒力A/H5N1禽流感在全球范围内传播，凸显了人流感大流行的潜在威胁。达菲和瑞乐沙是目前仅有的两种针对人类流感病毒神经氨酸酶（NA）的抗流感药物。耐药性出现的报道进一步使开发新型强效抗流感抑制剂成为当务之急。 A/H5N1 禽流感 NA 亚型的 X 射线晶体学研究（Russell, R. J. Nature 2006, 443, 45-49）表明存在两个遗传上不同的组，即组 1（N1、N4、N5 和 N8）和组 2（N2、N3、N6、N7 和 N9），其构象有很大不同。迄今为止，对其活性位点的详细比较为开发新型抗流感药物建立了最准确、最坚实的结构和机制的分子基础。本研究以禽流感病毒N1亚型（N1aA）的X射线晶体结构为模板，通过同源建模生成了人甲型流感病毒N1亚型（N1hA）的三维结构。通过将从头开始片段分子轨道（FMO）计算和三维定量构效关系与比较分子场分析（3D-QSAR CoMFA）建模相结合，进行了活性位点与其抑制剂之间的结合相互作用分析。结合基于对接的3D-QSAR CoMFA建模、分子表面特性（静电和空间）映射和FMO对相互作用分析，建立了一套新的受体-配体结合模型和生物亲和力预测模型，用于合理设计和虚拟筛选更有效的N1hA抑制剂。此外，N1hA和N1aA的loop-150的灵活性已通过一系列分子动力学模拟进行了检验。
Recently, the worldwide spread of A/H5N1 avian influenza with high virulence has highlighted the potential threat of human influenza pandemic. Tamiflu and Relenza are currently the only two anti-influenza drugs targeting the neuraminidase (NA) enzyme of human influenza virus. Reports of the emergence of drug resistance further make the development of new potent anti-influenza inhibitors a priority. The X-ray crystallographic study of A/H5N1 avian influenza NA subtypes (Russell, R. J. Nature 2006, 443, 45-49) has demonstrated that there exist two genetically distinct groups, group-1 (N1, N4, N5 and N8) and group-2 (N2, N3, N6, N7 and N9), whose conformations are substantially different. The detailed comparison of their active sites has established, heretofore, the most accurate and solid molecular basis of structure and mechanism for the development of new anti-influenza drugs. In the present study, a three-dimensional structure of N1 subtype of human influenza type A virus (N1hA) has been generated by homology modeling using the X-ray crystallographic structure of N1 subtype of avian influenza virus (N1aA) as the template. Binding interaction analysis between the active site and its inhibitors has been performed by combining ab initio fragment molecular orbital (FMO) calculations and three-dimensional quantitative structure-activity relationship with comparative molecular field analysis (3D-QSAR CoMFA) modeling. Integrated with docking-based 3D-QSAR CoMFA modeling, molecular surface property (electrostatic and steric) mapping and FMO pair interaction analysis, a set of new receptor-ligand binding models and bioaffinity predictive models for rational design and virtual screening of more potent inhibitors of N1hA are established. In addition, the flexibility of the loop-150 of N1hA and N1aA has been examined by a series of molecular dynamics simulations.