Isothiazoles as active-site inhibitors of HCV NS5B polymerase.
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.
Yan
Shunqi
S
Valeant Pharmaceutical Research and Development, 3300 Hyland Ave., Costa Mesa, CA 92626, USA. syan@valeant.com
Appleby
Todd
T
Gunic
Esmir
E
Shim
Jae Hoon
JH
Tasu
Tania
T
Kim
Hongwoo
H
Rong
Frank
F
Chen
Huaming
H
Hamatake
Robert
R
Wu
Jim Z
JZ
Hong
Zhi
Z
Yao
Nanhua
N
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
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