title: Computational analysis of de novo evolution of hepatitis C virus NS5B polymerase inhibitors.
abstract: HCV (Hepatitis C virus) that causes chronic liver disease. HCV NS5B RNA-dependent RNA polymerase (RbRp) and NS3 protease are able to affect virtual replication of genes. Computer-aided drug design (CADD) aims at designing new molecules with pharmacological activity. In this study, we used the Discovery Studio 2.0 program and the scoring function to estimate the Dock Score, piecewise linear potential 1 (PLP1), piecewise linear potential 2 (PLP2), and potential of mean force (PMF) score of novel compounds. In this way, novel compounds with "de novo evolution" can be found. Using the the pharmacophore features that are near the receptor pocket and the score functions to calculate scores for the ligand-receptor interaction, the new ligands were selected, developed and virtually placed in the binding site of the receptor. A new compound, EVO12, gave the best score, indicating that it may be an efficient polymerase inhibitor of HCV NS5B.
authors.affiliation: Department of Biological Science and Technology, China Medical University, No 91, Hsueh-Shih Road, Taichung 40402, Taiwan, ROC.
authors.forename: Po-Yuan
authors.initials: PY
authors.lastname: Chen
authors.forename: Wei-Tse
authors.initials: WT
authors.lastname: Hsu
authors.forename: Mien-De
authors.initials: MD
authors.lastname: Jhuo
authors.forename: Che-Yen
authors.initials: CY
authors.lastname: Ou
authors.forename: Tzu-Hurng
authors.initials: TH
authors.lastname: Cheng
authors.forename: Tzu-Ching
authors.initials: TC
authors.lastname: Shih
authors.forename: Chieh-Hsi
authors.initials: CH
authors.lastname: Wu
authors.forename: Rick Sai-Chuan
authors.initials: RS
authors.lastname: Wu
authors.forename: Te-Chun
authors.initials: TC
authors.lastname: Hsia
authors.forename: Jing-Gung
authors.initials: JG
authors.lastname: Chung
mesh_terms: D001665:Binding Sites; D017076:Computer-Aided Design; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D016174:Hepacivirus / Q000187:drug effects / Q000201:enzymology; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D012984:Software; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D004791:Enzyme Inhibitors; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase