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Current Pharmaceutical Design


ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

FDA-approved Drugs Selected Using Virtual Screening Bind Specifically to G-quadruplex DNA

Author(s): Daimel Castillo-Gonzalez, Gisselle Perez-Machado, Aurore Guedin, Jean-Louis Mergny and Miguel-Angel Cabrera-Perez

Volume 19, Issue 12, 2013

Page: [2164 - 2173] Pages: 10

DOI: 10.2174/1381612811319120004

Price: $65


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 Gquadruplex 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.

Keywords: FRET melting, G-quadruplex, QSAR, telomeres, virtual screening, oncogene promoters, FDA-approved compounds, prochloroperazine, promazine, duplex sequence

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