Document Detail

SAR and mode of action of novel non-nucleoside inhibitors of hepatitis C NS5b RNA polymerase.
MedLine Citation:
PMID:  16451069     Owner:  NLM     Status:  MEDLINE    
Novel non-nucleoside inhibitors of the HCV RNA polymerase (NS5b) with sub-micromolar biochemical potency have been identified which are selective for the inhibition of HCV NS5b over other polymerases. The structures of the complexes formed between several of these inhibitors and HCV NS5b were determined by X-ray crystallography, and the inhibitors were found to bind in an allosteric binding site separate from the active site. Structure-activity relationships and structural studies have identified the mechanism of action for compounds in this series, several of which possess drug-like properties, as unique, reversible, covalent inhibitors of HCV NS5b.
Jay P Powers; Derek E Piper; Yang Li; Veronica Mayorga; John Anzola; James M Chen; Juan C Jaen; Gary Lee; Jinqian Liu; M Greg Peterson; George R Tonn; Qiuping Ye; Nigel P C Walker; Zhulun Wang
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, Non-P.H.S.    
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  49     ISSN:  0022-2623     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2006 Feb 
Date Detail:
Created Date:  2006-02-02     Completed Date:  2006-03-29     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1034-46     Citation Subset:  IM    
Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA.
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MeSH Terms
Allosteric Site
Avian myeloblastosis virus / enzymology
Binding Sites
Crystallography, X-Ray
DNA-Directed RNA Polymerases / antagonists & inhibitors*,  chemistry*
Diarrhea Viruses, Bovine Viral / enzymology
Models, Molecular*
Protein Conformation
Reverse Transcriptase Inhibitors / chemical synthesis,  chemistry
Structure-Activity Relationship
Thiazoles / chemical synthesis*,  chemistry
Thiones / chemical synthesis*,  chemistry
Viral Nonstructural Proteins / antagonists & inhibitors*,  chemistry*
Reg. No./Substance:
0/NS-5 protein, hepatitis C virus; 0/Reverse Transcriptase Inhibitors; 0/Thiazoles; 0/Thiones; 0/Viral Nonstructural Proteins; EC RNA Polymerases

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