title: Small-molecule interferon inducers. Toward the comprehension of the molecular determinants through ligand-based approaches.
abstract: Hepatitis C is becoming an increasingly common cause of mortality especially in the HIV-coinfected group. Due to the efficacy of interferon (IFN) based therapy in the treatment of hepatitis C, various compounds possessing IFN-inducing activity have been hitherto reported. In the present study, we describe how steric, electrostatic, hydrophobic, and hydrogen-bonding interactions might influence the biological activity of a published set of IFN inducers, using a three-dimensional quantitative structure-activity relationship (3-D QSAR) approach. Analyses were conducted evaluating different series of compounds structurally related to 8-hydroxyadenines and 1H-imidazo[4,5-c]quinolines. A ligand-based alignment protocol in combination with the GRID/GOLPE approach was applied: 62 3-D QSAR models were derived using different GRID probes and several training sets. Performed 3-D QSAR investigations proved to be of good statistical value displaying r2, q2CV-LOO, and cross-validated SDEP values of 0.73, 0.61, 0.61 and 0.89, 0.64, 0.58 using the OH or the DRY probe, respectively. Additionally, the predictive performance was evaluated using an external test set of 20 compounds. Analyses of the resulting models led to the definition of a pharmacophore model that can be of interest to explain the observed affinities of known compounds as well as to design novel low molecular weight IFN inducers (IFNIs). To the best of our knowledge, this is the first 3-D QSAR application on IFN-inducing agents.
authors.affiliation: Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, P. le A. Moro 5, 00185, Rome, Italy.
authors.forename: Ira
authors.initials: I
authors.lastname: Musmuca
authors.forename: Silvia
authors.initials: S
authors.lastname: Simeoni
authors.forename: Antonia
authors.initials: A
authors.lastname: Caroli
authors.forename: Rino
authors.initials: R
authors.lastname: Ragno
mesh_terms: D003198:Computer Simulation; D015195:Drug Design; D007369:Interferon Inducers / Q000737:chemistry* / Q000494:pharmacology*; D008024:Ligands; D008954:Models, Biological; D008958:Models, Molecular; D015394:Molecular Structure; D021281:Quantitative Structure-Activity Relationship
chemical_list: D007369:Interferon Inducers; D008024:Ligands