| Autor: |
Di Santo R; Istituto Pasteur-Fondazione Cenci Bolognetti-Dipartimento di Studi Farmaceutici, University of Rome La Sapienza, P.le Aldo Moro 5, I-00185 Roma, Italy., Fermeglia M, Ferrone M, Paneni MS, Costi R, Artico M, Roux A, Gabriele M, Tardif KD, Siddiqui A, Pricl S |
| Jazyk: |
angličtina |
| Zdroj: |
Journal of medicinal chemistry [J Med Chem] 2005 Oct 06; Vol. 48 (20), pp. 6304-14. |
| DOI: |
10.1021/jm0504454 |
| Abstrakt: |
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. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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