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

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• 作者：Dr. Roberta Rocca ; Dr. Giosuè ; Costa ; Dr. Anna Artese ; Dr. Lucia Parrotta ; Prof. Francesco Ortuso ; Prof. Elias Maccioni ; Dr. Odra Pinato ; Dr. Maria Laura Greco ; Prof. Claudia Sissi ; Prof. Stefano Alcaro ; Dr. Simona Distinto and Dr. Federica Moraca
• 刊名：ChemMedChem
• 出版年：2016
• 出版时间：August 19, 2016
• 年：2016
• 卷：11
• 期：16
• 页码：1721-1733
• 全文大小：2843K
• ISSN：1860-7187

文摘

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.