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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
KeywordHcv Ns5b Benzothiadiazine Analogs Allosteric Site 3d-qsar Comfa Comsia Molecular Docking Molecular Dynamics
Source PublicationCURRENT MEDICINAL CHEMISTRY
2010-09-01
Volume17Issue:25Pages:2788-2803
Indexed BySCI
SubtypeArticle
WOS HeadingsScience & Technology ; Life Sciences & Biomedicine
WOS SubjectBiochemistry & Molecular Biology ; Chemistry, Medicinal ; Pharmacology & Pharmacy
WOS Research AreaBiochemistry & Molecular Biology ; Pharmacology & Pharmacy
WOS KeywordDEPENDENT RNA-POLYMERASE ; SIMILARITY INDEXES ANALYSIS ; NONSTRUCTURAL PROTEIN 5B ; FIELD ANALYSIS COMFA ; HCVNS5B POLYMERASE ; NONNUCLEOSIDE INHIBITORS ; 3D QSAR ; CRYSTAL-STRUCTURES ; ANALYSIS COMSIA ; SWISS-MODEL
AbstractIn 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.
Language英语
WOS IDWOS:000280507600008
Citation statistics
Cited Times:37[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Identifierhttp://cas-ir.dicp.ac.cn/handle/321008/142073
Collection中国科学院大连化学物理研究所
Affiliation1.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
GB/T 7714
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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