title: Discovery of novel HCV polymerase inhibitors using pharmacophore-based virtual screening.
abstract: We report the use of pharmacophore-based virtual screening as an efficient tool for the discovery of novel HCV polymerase inhibitors. A three-dimensional pharmacophore model for the HCV-796 binding site, NNI site IV inhibitor, to the enzyme was built by means of the structure-based focusing module in Cerius2 program. Using these models as a query for virtual screening, we produced a successful example of using pharmacophore-based virtual screening to identify novel compounds with HCV replicon assay through inhibition of HCV polymerization. Among the hit compounds, compounds 1 and 2 showed 56% and 48% inhibition of NS5B polymerization activity at 20 μM, respectively. In addition, compound 1 also exhibited replicon activity with EC(50) value of 2.16 μM. Following up the initial hit, we obtained derivatives of compound 1 and evaluated polymerization inhibition activity and HCV replicon assay. These results provide information necessary for the development of more potent NS5B inhibitors.
authors.affiliation: R&D Center, Equis & Zaroo Co., Ltd, Gyeonggi-do 443-766, Republic of Korea.
authors.forename: Nam Doo
authors.initials: ND
authors.lastname: Kim
authors.forename: Haarin
authors.initials: H
authors.lastname: Chun
authors.forename: Sang Jin
authors.initials: SJ
authors.lastname: Park
authors.forename: Jae Won
authors.initials: JW
authors.lastname: Yang
authors.forename: Jong Woo
authors.initials: JW
authors.lastname: Kim
authors.forename: Soon Kil
authors.initials: SK
authors.lastname: Ahn
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology*; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D008958:Models, Molecular; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase