Structure-based design of a novel thiazolone scaffold as HCV NS5B polymerase allosteric inhibitors.
A structure-based approach was performed to design a novel thiazolone scaffold as HCV NS5B inhibitors. A focused library was designed and docked by GOLD. One of the top-scored molecules was synthesized and shown to have similar potency to the initial hit. The X-ray complex structure was determined and validated our design rationale.
Yan
Shunqi
S
Valeant Pharmaceuticals Research and Development, 3300 Hyland Ave. Costa Mesa, CA 92626, USA. syan@valeant.com
Appleby
Todd
T
Larson
Gary
G
Wu
Jim Z
JZ
Hamatake
Robert
R
Hong
Zhi
Z
Yao
Nanhua
N
D000494:Allosteric Regulation; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D019295:Computational Biology; D018360:Crystallography, X-Ray; D012321:DNA-Directed RNA Polymerases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012324:RNA-Dependent RNA Polymerase
D000998:Antiviral Agents; D012321:DNA-Directed RNA Polymerases; D004791:Enzyme Inhibitors; D013844:Thiazoles; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase