title: Isothiazoles as active-site inhibitors of HCV NS5B polymerase.
abstract: Isothiazole analogs were discovered as a novel class of active-site inhibitors of HCV NS5B polymerase. The best compound has an IC(50) of 200 nM and EC(50) of 100 nM, which is a significant improvement over the starting inhibitor (1). The X-ray complex structure of 1 with HCV NS5B was obtained at a resolution of 2.2A, revealing that the inhibitor is covalently linked with Cys 366 of the 'primer-grip'. Furthermore, it makes considerable contacts with the C-terminus, beta-loop, and more importantly, to the active-site of the enzyme. The uniqueness of this binding mode offers a new insight for the rational design of novel inhibitors for HCV NS5B polymerase.
authors.affiliation: Valeant Pharmaceutical Research and Development, 3300 Hyland Ave., Costa Mesa, CA 92626, USA. syan@valeant.com
authors.forename: Shunqi
authors.initials: S
authors.lastname: Yan
authors.forename: Todd
authors.initials: T
authors.lastname: Appleby
authors.forename: Esmir
authors.initials: E
authors.lastname: Gunic
authors.forename: Jae Hoon
authors.initials: JH
authors.lastname: Shim
authors.forename: Tania
authors.initials: T
authors.lastname: Tasu
authors.forename: Hongwoo
authors.initials: H
authors.lastname: Kim
authors.forename: Frank
authors.initials: F
authors.lastname: Rong
authors.forename: Huaming
authors.initials: H
authors.lastname: Chen
authors.forename: Robert
authors.initials: R
authors.lastname: Hamatake
authors.forename: Jim Z
authors.initials: JZ
authors.lastname: Wu
authors.forename: Zhi
authors.initials: Z
authors.lastname: Hong
authors.forename: Nanhua
authors.initials: N
authors.lastname: Yao
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D008968:Molecular Conformation; D011487:Protein Conformation; D013844:Thiazoles / Q000737:chemistry* / Q000494:pharmacology*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D013844:Thiazoles; D017361:Viral Nonstructural Proteins; C518992:4-cyano-3-hydroxy-5-(3,5-bis(trifluoromethyl)benzylamino)isothiazole; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase