title: SAR and mode of action of novel non-nucleoside inhibitors of hepatitis C NS5b RNA polymerase.
abstract: Novel non-nucleoside inhibitors of the HCV RNA polymerase (NS5b) with sub-micromolar biochemical potency have been identified which are selective for the inhibition of HCV NS5b over other polymerases. The structures of the complexes formed between several of these inhibitors and HCV NS5b were determined by X-ray crystallography, and the inhibitors were found to bind in an allosteric binding site separate from the active site. Structure-activity relationships and structural studies have identified the mechanism of action for compounds in this series, several of which possess drug-like properties, as unique, reversible, covalent inhibitors of HCV NS5b.
authors.affiliation: Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA. jppowers@amgen.com
authors.forename: Jay P
authors.initials: JP
authors.lastname: Powers
authors.forename: Derek E
authors.initials: DE
authors.lastname: Piper
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.forename: Veronica
authors.initials: V
authors.lastname: Mayorga
authors.forename: John
authors.initials: J
authors.lastname: Anzola
authors.forename: James M
authors.initials: JM
authors.lastname: Chen
authors.forename: Juan C
authors.initials: JC
authors.lastname: Jaen
authors.forename: Gary
authors.initials: G
authors.lastname: Lee
authors.forename: Jinqian
authors.initials: J
authors.lastname: Liu
authors.forename: M Greg
authors.initials: MG
authors.lastname: Peterson
authors.forename: George R
authors.initials: GR
authors.lastname: Tonn
authors.forename: Qiuping
authors.initials: Q
authors.lastname: Ye
authors.forename: Nigel P C
authors.initials: NP
authors.lastname: Walker
authors.forename: Zhulun
authors.initials: Z
authors.lastname: Wang
mesh_terms: D000495:Allosteric Site; D009189:Avian Myeloblastosis Virus / Q000201:enzymology; D001665:Binding Sites; D018360:Crystallography, X-Ray; D012321:DNA-Directed RNA Polymerases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D001908:Diarrhea Viruses, Bovine Viral / Q000201:enzymology; D008958:Models, Molecular; D011487:Protein Conformation; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry; D013871:Thiones / Q000138:chemical synthesis* / Q000737:chemistry; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D012321:DNA-Directed RNA Polymerases; D018894:Reverse Transcriptase Inhibitors; D013844:Thiazoles; D013871:Thiones; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase