Document Detail

Simple but highly effective three-dimensional chemical-feature-based pharmacophore model for diketo acid derivatives as hepatitis C virus RNA-dependent RNA polymerase inhibitors.
MedLine Citation:
PMID:  16190757     Owner:  NLM     Status:  MEDLINE    
A molecular modeling strategy using aryl diketo acid (ADK) derivatives recently reported in the literature as hepatitis C virus (HCV) polymerase inhibitors was designed. A 3D chemical-feature-based pharmacophore model was developed using Catalyst software, which produced 10 pharmacophore hypotheses. The top-ranked one (Hypo 1), characterized by a high correlation coefficient (r = 0.965), consisted of two hydrogen bond acceptors, one negative ionizable moiety, and two hydrophobic aromatics. This model was used to predict the anti-RNA-dependent RNA polymerase (anti-RdRp) activity of 6-(1-arylmethylpyrrol-2-yl)-1,4-dioxo-5-hexenoic acids and other ADK derivatives previously synthesized in our laboratories as HIV-1 integrase inhibitors. Furthermore, the experimental IC50 values of 9 compounds, tested in vitro against recombinant HCV polymerase, were compared with the corresponding values predicted using Hypo1. A good agreement between experimental and simulated data was obtained. The results demonstrate that the hypothesis derived in this study can be considered to be a useful tool in designing new leads based on ADK scaffolds as HCV RdRp inhibitors.
Roberto Di Santo; Maurizio Fermeglia; Marco Ferrone; Maria Silvia Paneni; Roberta Costi; Marino Artico; Alessandra Roux; Mirko Gabriele; Keith D Tardif; Aleem Siddiqui; Sabrina Pricl
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  48     ISSN:  0022-2623     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2005 Oct 
Date Detail:
Created Date:  2005-09-29     Completed Date:  2005-11-28     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:  6304-14     Citation Subset:  IM    
Istituto Pasteur-Fondazione Cenci Bolognetti-Dipartimento di Studi Farmaceutici, University of Rome La Sapienza, P.le Aldo Moro 5, I-00185 Roma, Italy.
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MeSH Terms
Antiviral Agents / chemistry*
Drug Design
Enzyme Inhibitors / chemistry*
Hepacivirus / enzymology*
Keto Acids / chemistry*
Models, Molecular
Molecular Structure
Quantitative Structure-Activity Relationship
RNA Replicase / antagonists & inhibitors*,  chemistry*
Reg. No./Substance:
0/Antiviral Agents; 0/Enzyme Inhibitors; 0/Keto Acids; EC Replicase

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