Discovery of novel dialkyl substituted thiophene inhibitors of HCV by in silico screening of the NS5B RdRp.
A novel 5,4-dialkyl substituted thiophene was discovered by in silico screening of the 3D polymerase crystal structure (1GX6) that demonstrated single digit micromolar HCV inhibition activity in the replicon assay and dose-dependent inhibition in the replicase complex assay. Subsequently, SAR was explored with a small set of dialkyl and tetrahydro-benzo thiophenes. Since these thiophenes inhibit synthesis of both, single- and double-stranded RNAs, their mechanism of action is distinct from other known HCV inhibitors.
Louise-May
Shirley
S
Achillion Pharmaceuticals, 300 George Street, New Haven, CT 06511, USA.
Yang
Wengang
W
Nie
Xingtie
X
Liu
Dongmei
D
Deshpande
Milind S
MS
Phadke
Avinash S
AS
Huang
Mingjun
M
Agarwal
Atul
A
D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology; D008954:Models, Biological; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology*; D017361:Viral Nonstructural Proteins / Q000187:drug effects*; D012324:RNA-Dependent RNA Polymerase
D013876:Thiophenes; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase