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Studies of Benzothiadiazine Derivatives as Hepatitis C Virus NS5B Polymerase Inhibitors Using 3D-QSAR, Molecular Docking and Molecular Dynamics
Wang, X.1; Yang, W.1; Xu, X.1; Zhang, H.1; Li, Y.2; Wang, Y.1,3
关键词Hcv Ns5b Benzothiadiazine Analogs Allosteric Site 3d-qsar Comfa Comsia Molecular Docking Molecular Dynamics
刊名CURRENT MEDICINAL CHEMISTRY
2010-09-01
17期:25页:2788-2803
收录类别SCI
文章类型Article
WOS标题词Science & Technology ; Life Sciences & Biomedicine
类目[WOS]Biochemistry & Molecular Biology ; Chemistry, Medicinal ; Pharmacology & Pharmacy
研究领域[WOS]Biochemistry & Molecular Biology ; Pharmacology & Pharmacy
关键词[WOS]DEPENDENT RNA-POLYMERASE ; SIMILARITY INDEXES ANALYSIS ; NONSTRUCTURAL PROTEIN 5B ; FIELD ANALYSIS COMFA ; HCVNS5B POLYMERASE ; NONNUCLEOSIDE INHIBITORS ; 3D QSAR ; CRYSTAL-STRUCTURES ; ANALYSIS COMSIA ; SWISS-MODEL
英文摘要In order to explore the structure-activity correlation of benzothiadiazine series as inhibitors of genotype 1a HCV polymerase, a set of ligand-and receptor-based 3D-QSAR models were, for the first time, developed in the present work employing Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Index Analysis (CoMSIA) for 239 promising molecules. In addition, homology modeling, docking analysis, and molecular dynamics simulation (MD) were also applied to elucidate the probable binding modes of these inhibitors at the allosteric site of the enzyme. The statistical model validations assure the reliability of the obtained QSAR models. Changes in the binding affinity of the inhibitors attributing to modifications in the aromatic rings could be rationalized by the steric, electrostatic, hydrophobic, and hydrogen bond acceptor properties. (i) Hydrophobic substituents with similar size of benzo group like isosteres are preferential at positions 1 and 2 (ring B of benzothiadiazines). (ii) Substituents at position-3 containing a linear alkyl chain (four or five carbon atoms) or a branched alkyl chain (five-eight carbons) can increase the inhibitory activity by one to two orders of magnitude. (iii) A polar substituent like methanesulfonamide group at position-14 can enhance the activity of the drug by providing a hydrogen bonding interaction with the protein target. The results obtained from this work provide important guidelines in design of novel benzothiadiazine analogs as inhibitors of HCV genotype 1a NS5B.
语种英语
WOS记录号WOS:000280507600008
引用统计
文献类型期刊论文
条目标识符http://cas-ir.dicp.ac.cn/handle/321008/142150
专题中国科学院大连化学物理研究所
作者单位1.NW A&F Univ, Ctr Bioinformat, Yangling 712100, Shaanxi, Peoples R China
2.Dalian Univ Technol, Sch Chem Engn, Dalian 116012, Liaoning, Peoples R China
3.Chinese Acad Sci, Dalian Inst Chem Phys, Lab Pharmaceut Resource Discovery, Grad Sch, Dalian 116023, Liaoning, Peoples R China
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Wang, X.,Yang, W.,Xu, X.,et al. Studies of Benzothiadiazine Derivatives as Hepatitis C Virus NS5B Polymerase Inhibitors Using 3D-QSAR, Molecular Docking and Molecular Dynamics[J]. CURRENT MEDICINAL CHEMISTRY,2010,17(25):2788-2803.
APA Wang, X.,Yang, W.,Xu, X.,Zhang, H.,Li, Y.,&Wang, Y..(2010).Studies of Benzothiadiazine Derivatives as Hepatitis C Virus NS5B Polymerase Inhibitors Using 3D-QSAR, Molecular Docking and Molecular Dynamics.CURRENT MEDICINAL CHEMISTRY,17(25),2788-2803.
MLA Wang, X.,et al."Studies of Benzothiadiazine Derivatives as Hepatitis C Virus NS5B Polymerase Inhibitors Using 3D-QSAR, Molecular Docking and Molecular Dynamics".CURRENT MEDICINAL CHEMISTRY 17.25(2010):2788-2803.
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