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.

journal_name

Curr Pharm Des

authors

Castillo-González D,Pérez-Machado G,Guédin A,Mergny JL,Cabrera-Pérez MA

doi

10.2174/1381612811319120004

subject

Has Abstract

pub_date

2013-01-01 00:00:00

pages

2164-73

issue

12

eissn

1381-6128

issn

1873-4286

pii

CPD-EPUB-20120924-18

journal_volume

19

pub_type

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