Structure-based design of novel HCV NS5B thumb pocket 2 allosteric inhibitors with submicromolar gt1 replicon potency: Discovery of a quinazolinone chemotype

We describe the structure-based design of a novel lead chemotype that binds to thumb pocket 2 of HCV NS5B polymerase and inhibits cell-based gt1 subgenomic reporter replicons at sub-micromolar concentrations (EC50

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2013-07, Vol.23 (14), p.4132-4140
Main Authors: Beaulieu, Pierre L., Coulombe, René, Duan, Jianmin, Fazal, Gulrez, Godbout, Cédrickx, Hucke, Oliver, Jakalian, Araz, Joly, Marc-André, Lepage, Olivier, Llinàs-Brunet, Montse, Naud, Julie, Poirier, Martin, Rioux, Nathalie, Thavonekham, Bounkham, Kukolj, George, Stammers, Timothy A.
Format: Article
Language:English
Subjects:
Allosteric inhibition
Allosteric properties
Allosteric Regulation
Animals
Antiviral Agents - chemical synthesis
Antiviral Agents - chemistry
Antiviral Agents - pharmacokinetics
Binding Sites
Crystallography, X-Ray
Drug Design
Drug Evaluation, Preclinical
Half-Life
HCV NS5B polymerase
Hepacivirus - enzymology
Hepacivirus - physiology
Hepatitis C virus
Molecular Docking Simulation
Non-nucleoside inhibitor
ortho-Aminobenzoates - chemistry
Protein Structure, Tertiary
Quinazolinones - chemical synthesis
Quinazolinones - chemistry
Quinazolinones - pharmacokinetics
Rats
Structure-Activity Relationship
Structure-based drug design
Thumb pocket 2
Viral Nonstructural Proteins - antagonists & inhibitors
Viral Nonstructural Proteins - metabolism
Virus Replication - drug effects
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Description
Summary:We describe the structure-based design of a novel lead chemotype that binds to thumb pocket 2 of HCV NS5B polymerase and inhibits cell-based gt1 subgenomic reporter replicons at sub-micromolar concentrations (EC50
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2013.05.037