title: Optimized Virtual Screening Workflow for the Identification of Novel G-Quadruplex Ligands.
abstract: G-quadruplexes, alternative DNA secondary structures present in telomeres, emerge as promising targets for the treatment of cancer, because they prevent telomere elongation and accordingly cell proliferation. Within this study, theoretically validated pharmacophore- and shape-based models as well as a theoretically validated docking protocol were generated and applied in parallel for virtual screening and the identification of novel G-quadruplex ligands. Top-ranked hits retrieved with all methods independently and in addition in a consensus approach were selected for biological testing. Of the 32 tested virtual hits seven selectively stabilized G-quadruplexes over duplex DNA in the fluorescence melting assay. For the five most active compounds, chemically closely related analogues were collected and subjected to in vitro analysis. Thereby, seven further novel G-quadruplex ligands could be identified. These molecules do not only represent novel scaffolds, but some of them are in addition even more potent G-quadruplex stabilizers than the established reference compound berberine. This study proposes an optimized in silico workflow for the identification of novel G-quadruplex stabilizers, which can also be applied in future studies. In addition, structurally novel and promising lead candidates with strong and selective G-quadruplex stabilizing properties are reported.
authors: Computer-Aided Molecular Design Group, Institute of Pharmacy/Pharmaceutical Chemistry and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck , Innrain 80-82, 6020 Innsbruck, Austria.
authors: Teresa
authors: T
authors: Kaserer
authors: Department of Pharmaceutical and Pharmacological Sciences, University of Padova , via Marzolo 5, 35131 Padova, Italy.
authors: Riccardo
authors: R
authors: Rigo
authors: Computer-Aided Molecular Design Group, Institute of Pharmacy/Pharmaceutical Chemistry and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck , Innrain 80-82, 6020 Innsbruck, Austria.
authors: Philipp
authors: P
authors: Schuster
authors: Dipartimento di Scienze della Salute, Università "Magna Graecia" di Catanzaro , Campus "S. Venuta", Viale Europa, 88100 Catanzaro, Italy.
authors: Stefano
authors: S
authors: Alcaro
authors: Department of Pharmaceutical and Pharmacological Sciences, University of Padova , via Marzolo 5, 35131 Padova, Italy.
authors: Claudia
authors: C
authors: Sissi
authors: Computer-Aided Molecular Design Group, Institute of Pharmacy/Pharmaceutical Chemistry and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck , Innrain 80-82, 6020 Innsbruck, Austria.
authors: Daniela
authors: D
authors: Schuster
mesh_terms: D005453:Fluorescence; D054856:G-Quadruplexes; D008024:Ligands; D008958:Models, Molecular; D057188:Workflow
chemical_list: D008024:Ligands