Fragment-based discovery of hepatitis C virus NS5b RNA polymerase inhibitors

• Published in: Bioorganic & medicinal chemistry Vol. 18; no. 9; pp. 2990 - 2995
• Main Authors: Antonysamy, Stephen S., Aubol, Brandon, Blaney, Jeff, Browner, Michelle F., Giannetti, Anthony M., Harris, Seth F., Hébert, Normand, Hendle, Jörg, Hopkins, Stephanie, Jefferson, Elizabeth, Kissinger, Charles, Leveque, Vincent, Marciano, David, McGee, Ethel, Nájera, Isabel, Nolan, Brian, Tomimoto, Masaki, Torres, Eduardo, Wright, Tobi
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.05.2008; Elsevier
• Subjects: 60 APPLIED LIFE SCIENCES; AFFINITY; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antiviral Agents - chemical synthesis; Antiviral Agents - therapeutic use; BASIC BIOLOGICAL SCIENCES; Binding Sites; BIOCHEMISTRY; Biological and medical sciences; Crystallography, X-Ray; DNA-Directed RNA Polymerases - antagonists & inhibitors; Enzyme Activation; ENZYMES; Fragment screening; HCV; Hepacivirus - chemistry; HEPATITIS; Hepatitis C - enzymology; Hepatitis C virus; INHIBITION; Medical sciences; NS5b; NUCLEOSIDES; Pharmacology. Drug treatments; PLASMONS; Protein crystallography; REPLICONS; RESONANCE; RNA POLYMERASES; Structure-Activity Relationship; Surface Plasmon Resonance; Viral Nonstructural Proteins - chemistry; Viral Nonstructural Proteins - pharmacology; Virus Replication - physiology; Fragment screening; HCV; Protein crystallography; NS5b; Non nucleoside compound; Crystallography; Modeling; Structure activity relation; Piperidine derivatives; Molecular model; Pyrazole derivatives; Antiviral; Ureas; Bromine Organic compounds; Enzyme; Aminoamide; Transferases; Benzene derivatives; Virtual screening; Enzyme inhibitor; Inhibitor enzyme complex; In vitro; RNA-directed RNA polymerase; Virus; Nucleotidyltransferases; Carboxamide; Anthranilic acid derivatives; Flaviviridae; Hepatitis C virus; Hepacivirus
• ISSN: 0960-894X; 0968-0896; 1464-3405; 1464-3405; 1464-3391
• DOI: 10.1016/j.bmcl.2008.03.056

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 ∼1–10 mM binding affinity ( K D) were iteratively optimized to give leads with ∼200 nM biochemical activity and low μM cellular activity in a Replicon assay.