title: Hit Identification of a Novel Dual Binder for h-telo/c-myc G-Quadruplex by a Combination of Pharmacophore Structure-Based Virtual Screening and Docking Refinement.
abstract: It is well known that G-quadruplexes are targets of great interest for their roles in crucial biological processes, such as aging and cancer. Hence, a promising strategy for anticancer drug therapy is the stabilization of these structures by small molecules. We report a high-throughput in silico screening of commercial libraries from several different vendors by means of a combined structure-based pharmacophore model approach followed by docking simulations. The compounds selected by the virtual screening procedure were then tested for their ability to interact with human telomeric G-quadruplex folding by circular dichroism, fluorescence spectroscopy, and fluorescence intercalator displacement. Our approach resulted in the identification of a 13-[(dimethylamino)methyl]-12-hydroxy-8H-benzo[c]indolo[3,2,1-ij][1,5]naphthyridin-8-one derivative as a novel promising stabilizer of G-quadruplex structures within the human telomeric and the c-myc promoter sequences.
authors.affiliation: Dipartimento di Scienze della Salute, Università degli Studi "Magna Graecia" di Catanzaro, Campus "Salvatore Venuta", Viale Europa, 88100, Catanzaro, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Rocca
authors.affiliation: Dipartimento di Scienze della Salute, Università degli Studi "Magna Graecia" di Catanzaro, Campus "Salvatore Venuta", Viale Europa, 88100, Catanzaro, Italy. gcosta@unicz.it.
authors.forename: Giosuè
authors.identifier: 0000-0003-0947-9479
authors.initials: G
authors.lastname: Costa
authors.affiliation: Dipartimento di Scienze della Salute, Università degli Studi "Magna Graecia" di Catanzaro, Campus "Salvatore Venuta", Viale Europa, 88100, Catanzaro, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Artese
authors.affiliation: Dipartimento di Scienze della Salute, Università degli Studi "Magna Graecia" di Catanzaro, Campus "Salvatore Venuta", Viale Europa, 88100, Catanzaro, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Parrotta
authors.affiliation: Dipartimento di Scienze della Salute, Università degli Studi "Magna Graecia" di Catanzaro, Campus "Salvatore Venuta", Viale Europa, 88100, Catanzaro, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Ortuso
authors.affiliation: Department of Life and Environment Sciences, University of Cagliari, Via Ospedale 72, 09124, Cagliari, Italy.
authors.forename: Elias
authors.initials: E
authors.lastname: Maccioni
authors.affiliation: Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Via Marzolo 5, 35131, Padova, Italy.
authors.forename: Odra
authors.initials: O
authors.lastname: Pinato
authors.affiliation: Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Via Marzolo 5, 35131, Padova, Italy.
authors.forename: Maria Laura
authors.initials: ML
authors.lastname: Greco
authors.affiliation: Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Via Marzolo 5, 35131, Padova, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Sissi
authors.affiliation: Dipartimento di Scienze della Salute, Università degli Studi "Magna Graecia" di Catanzaro, Campus "Salvatore Venuta", Viale Europa, 88100, Catanzaro, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Alcaro
authors.affiliation: Department of Life and Environment Sciences, University of Cagliari, Via Ospedale 72, 09124, Cagliari, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Distinto
authors.affiliation: Dipartimento di Scienze della Salute, Università degli Studi "Magna Graecia" di Catanzaro, Campus "Salvatore Venuta", Viale Europa, 88100, Catanzaro, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Moraca
mesh_terms: D004353:Drug Evaluation, Preclinical; D054856:G-Quadruplexes / Q000187:drug effects*; D016259:Genes, myc / Q000187:drug effects*; D006801:Humans; D062105:Molecular Docking Simulation; D011401:Promoter Regions, Genetic / Q000187:drug effects*
keywords: FRET; G-quadruplexes; circular dichroism; molecular modeling; virtual screening