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题名: Studies of Benzothiadiazine Derivatives as Hepatitis C Virus NS5B Polymerase Inhibitors Using 3D-QSAR, Molecular Docking and Molecular Dynamics
作者: 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
发表日期: 2010-09-01
卷: 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
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.
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
语种: 英语
WOS记录号: WOS:000280507600008
Citation statistics: 
内容类型: 期刊论文
URI标识: http://cas-ir.dicp.ac.cn/handle/321008/142073
Appears in Collections:中国科学院大连化学物理研究所_期刊论文

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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

Recommended Citation:
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.
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