title: Computer-aided identification, synthesis and evaluation of substituted thienopyrimidines as novel inhibitors of HCV replication.
abstract: A structure-based virtual screening technique was applied to the study of the HCV NS3 helicase, with the aim to find novel inhibitors of the HCV replication. A library of ∼450000 commercially available compounds was analysed in silico and 21 structures were selected for biological evaluation in the HCV replicon assay. One hit characterized by a substituted thieno-pyrimidine scaffold was found to inhibit the viral replication with an EC50 value in the sub-micromolar range and a good selectivity index. Different series of novel thieno-pyrimidine derivatives were designed and synthesised; several new structures showed antiviral activity in the low or sub-micromolar range.
authors.affiliation: Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff, King Edward VII Avenue, Cardiff, CF103NB, UK. Electronic address: bassettom@cardiff.ac.uk.
authors.forename: Marcella
authors.initials: M
authors.lastname: Bassetto
authors.affiliation: Rega Institute for Medical Research, University of Leuven, Belgium.
authors.forename: Pieter
authors.initials: P
authors.lastname: Leyssen
authors.affiliation: Rega Institute for Medical Research, University of Leuven, Belgium.
authors.forename: Johan
authors.initials: J
authors.lastname: Neyts
authors.affiliation: Department of Chemistry & Biochemistry, University of Wisconsin- Milwaukee, Milwaukee, WI 53211, USA.
authors.forename: Mark M
authors.initials: MM
authors.lastname: Yerukhimovich
authors.affiliation: Department of Chemistry & Biochemistry, University of Wisconsin- Milwaukee, Milwaukee, WI 53211, USA.
authors.forename: David N
authors.initials: DN
authors.lastname: Frick
authors.affiliation: Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff, King Edward VII Avenue, Cardiff, CF103NB, UK.
authors.forename: Andrea
authors.initials: A
authors.lastname: Brancale
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology; D017076:Computer-Aided Design; D015195:Drug Design; D016174:Hepacivirus / Q000187:drug effects / Q000254:growth & development; D006526:Hepatitis C / Q000188:drug therapy; D046609:Libraries, Digital; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D014779:Virus Replication / Q000187:drug effects*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D011743:Pyrimidines; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C476003:thienopyrimidine
keywords: Anti-HCV activity; Structure-based virtual screening; Substituted thieno-pyrimidines