title: Insight into the structural requirements of benzothiadiazine scaffold-based derivatives as hepatitis C virus NS5B polymerase inhibitors using 3D-QSAR, molecular docking and molecular dynamics.
abstract: Hepatitis C virus (HCV) infection is a significant world health threat with frequently ineffective problem existed in the present treatment, thus representing a major unmet medical need. The nonstructural viral protein 5B (NS5B), one of the best-studied polymerase, has emerged as an attractive target for the development of novel therapeutics against hepatitis C virus. In this work, both ligand- and receptor- based three-dimensional quantitative structure  activity relationship (3D-QSAR) studies were carried out using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques on 360 benzothiadiazine scaffold-based derivatives as HCV GT-1b NS5B polymerase allosteric inhibitors. The resultant optimum 3D-QSAR model exhibited R(2)(ev) of 0.54, R(2)(nev) of 0.72 and the predictive ability was validated by using an independent test set of 90 compounds which gave R(2)(pred) value of 0.64. In addition, 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. Interpretation of the 3D contour maps in context of the topology of the allosteric binding site of NS5B provided insight into NS5B-inhibitor interactions. The information obtained from this work can be utilized to accurately predict the binding affinity of related analogues and also facilitate the future rational design of novel inhibitors with improved activity.
authors.affiliation: School of Chemical Engineering, Dalian University of Technology, Dalian, Liaoning, 116024, China.
authors.forename: H-X
authors.initials: HX
authors.lastname: Zhang
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.forename: Z-T
authors.initials: ZT
authors.lastname: Xiao
authors.forename: Y-H
authors.initials: YH
authors.lastname: Wang
mesh_terms: D000818:Animals; D001581:Benzothiadiazines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D001665:Binding Sites; D015195:Drug Design; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D016174:Hepacivirus / Q000737:chemistry* / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D006526:Hepatitis C / Q000188:drug therapy* / Q000453:epidemiology / Q000235:genetics; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D058990:Molecular Targeted Therapy; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D054852:Small Molecule Libraries; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: D001581:Benzothiadiazines; D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; D017361:Viral Nonstructural Proteins