title: Discovery of novel dialkyl substituted thiophene inhibitors of HCV by in silico screening of the NS5B RdRp.
abstract: A novel 5,4-dialkyl substituted thiophene was discovered by in silico screening of the 3D polymerase crystal structure (1GX6) that demonstrated single digit micromolar HCV inhibition activity in the replicon assay and dose-dependent inhibition in the replicase complex assay. Subsequently, SAR was explored with a small set of dialkyl and tetrahydro-benzo thiophenes. Since these thiophenes inhibit synthesis of both, single- and double-stranded RNAs, their mechanism of action is distinct from other known HCV inhibitors.
authors.affiliation: Achillion Pharmaceuticals, 300 George Street, New Haven, CT 06511, USA.
authors.forename: Shirley
authors.initials: S
authors.lastname: Louise-May
authors.forename: Wengang
authors.initials: W
authors.lastname: Yang
authors.forename: Xingtie
authors.initials: X
authors.lastname: Nie
authors.forename: Dongmei
authors.initials: D
authors.lastname: Liu
authors.forename: Milind S
authors.initials: MS
authors.lastname: Deshpande
authors.forename: Avinash S
authors.initials: AS
authors.lastname: Phadke
authors.forename: Mingjun
authors.initials: M
authors.lastname: Huang
authors.forename: Atul
authors.initials: A
authors.lastname: Agarwal
mesh_terms: D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology; D008954:Models, Biological; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology*; D017361:Viral Nonstructural Proteins / Q000187:drug effects*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D013876:Thiophenes; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase