1. Fragment-based discovery of hepatitis C virus NS5b RNA polymerase inhibitors
- Author
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Masaki Tomimoto, Stephanie Hopkins, Brian E. Nolan, Jeff Blaney, Anthony M. Giannetti, Seth F. Harris, Michelle F. Browner, Normand Hebert, Jorg Hendle, Eduardo Torres, Brandon E. Aubol, Ethel McGee, David Marciano, Tobi A Wright, Isabel Najera, Elizabeth A. Jefferson, Charles R. Kissinger, Vincent Leveque, and Stephen Suresh Antonysamy
- Subjects
Hepatitis C virus ,Clinical Biochemistry ,Pharmaceutical Science ,Hepacivirus ,Viral Nonstructural Proteins ,Crystallography, X-Ray ,Virus Replication ,medicine.disease_cause ,Antiviral Agents ,Biochemistry ,Structure-Activity Relationship ,chemistry.chemical_compound ,Enzyme activator ,RNA polymerase ,Drug Discovery ,medicine ,Replicon ,Binding site ,Molecular Biology ,NS5B ,chemistry.chemical_classification ,Binding Sites ,biology ,Organic Chemistry ,DNA-Directed RNA Polymerases ,Surface Plasmon Resonance ,Hepatitis C ,Molecular biology ,Enzyme Activation ,Enzyme ,chemistry ,Enzyme inhibitor ,biology.protein ,Molecular Medicine - Abstract
Non-nucleoside inhibitors of HCV NS5b RNA polymerase were discovered by a fragment-based lead discovery approach, beginning with crystallographic fragment screening. The NS5b binding affinity and biochemical activity of fragment hits and inhibitors was determined by surface plasmon resonance (Biacore) and an enzyme inhibition assay, respectively. Crystallographic fragment screening hits with approximately 1-10mM binding affinity (K(D)) were iteratively optimized to give leads with approximately 200nM biochemical activity and low microM cellular activity in a Replicon assay.
- Published
- 2008