title: FDA-approved drugs selected using virtual screening bind specifically to G-quadruplex DNA.
abstract: Guanine-rich sequences found in telomeres and oncogene promoters have the ability to form G-quadruplex structures. In this paper we describe the use of a virtual screening assay to search a database of FDA-approved compounds for compounds with the potential to bind G-quadruplex DNA. More than 750 telomerase inhibitors were identified in a literature search as acting through G-quadruplex stabilization, and from evaluation of these compounds, theoretical models capable of discriminating new compounds that bind G-quadruplex DNA were developed. Six compounds predicted to bind to the G-quadruplex structure were tested for their ability to bind to the human telomeric DNA sequence. Prochloroperazine, promazine, and chlorpromazine stabilized the G-quadruplex structure as determined by fluorescence resonance energy transfer techniques. These compounds also bound to promoter sequences of oncogenes such as c-myc and K-ras. Amitriptyline, imipramine, and loxapine were less stabilizing but did bind to the G-quadruplex. The ability of prochloroperazine, promazine, and chlorpromazine to recognize G-quadruplex structures was confirmed using a fluorescent intercalator displacement assay, in which displacement of thiazole orange from G-quadruplex structures was demonstrated. Interestingly, these compounds exhibited selectivity for the G-quadruplex structure as all had poor affinity for the duplex sequence.
authors.affiliation: Department of Pharmacy, Central University of Las Villas, Santa Clara 54830, Villa Clara, Cuba. daimelc@gmail.com
authors.forename: Dáimel
authors.initials: D
authors.lastname: Castillo-González
authors.forename: Gisselle
authors.initials: G
authors.lastname: Pérez-Machado
authors.forename: Aurore
authors.initials: A
authors.lastname: Guédin
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Mergny
authors.forename: Miguel-Angel
authors.initials: MA
authors.lastname: Cabrera-Pérez
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D019295:Computational Biology; D062313:Databases, Pharmaceutical; D017277:Drug Approval; D058492:Drug Repositioning; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D054856:G-Quadruplexes / Q000187:drug effects*; D006801:Humans; D007364:Intercalating Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D009857:Oncogenes / Q000187:drug effects; D055553:Prescription Drugs / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000187:drug effects; D021281:Quantitative Structure-Activity Relationship; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007364:Intercalating Agents; D008024:Ligands; D055553:Prescription Drugs; C509186:TERT protein, human; D019098:Telomerase