title: Simple but highly effective three-dimensional chemical-feature-based pharmacophore model for diketo acid derivatives as hepatitis C virus RNA-dependent RNA polymerase inhibitors.
abstract: 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.
authors.affiliation: Istituto Pasteur-Fondazione Cenci Bolognetti-Dipartimento di Studi Farmaceutici, University of Rome La Sapienza, P.le Aldo Moro 5, I-00185 Roma, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Di Santo
authors.forename: Maurizio
authors.initials: M
authors.lastname: Fermeglia
authors.forename: Marco
authors.initials: M
authors.lastname: Ferrone
authors.forename: Maria Silvia
authors.initials: MS
authors.lastname: Paneni
authors.forename: Roberta
authors.initials: R
authors.lastname: Costi
authors.forename: Marino
authors.initials: M
authors.lastname: Artico
authors.forename: Alessandra
authors.initials: A
authors.lastname: Roux
authors.forename: Mirko
authors.initials: M
authors.lastname: Gabriele
authors.forename: Keith D
authors.initials: KD
authors.lastname: Tardif
authors.forename: Aleem
authors.initials: A
authors.lastname: Siddiqui
authors.forename: Sabrina
authors.initials: S
authors.lastname: Pricl
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry*; D016174:Hepacivirus / Q000201:enzymology*; D007651:Keto Acids / Q000737:chemistry*; D008958:Models, Molecular; D015394:Molecular Structure; D021281:Quantitative Structure-Activity Relationship; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors* / Q000737:chemistry*
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D007651:Keto Acids; D012324:RNA-Dependent RNA Polymerase