Tandem application of virtual screening and NMR experiments in the discovery of brand new DNA quadruplex groove binders.
In the past decade, DNA G-quadruplexes have come into the limelight thanks to their biological implications and to their potential druggability in anticancer therapy. In particular, it has been found that small molecules that stabilize G-quadruplex structures are effective inhibitors of telomerase which plays a critical role in tumorigenesis. So far, the quadruplex groove recognition, which is expected to give a higher degree of selectivity over the other DNA structures, has been demonstrated for very few compounds. Thus with the aim of detecting new and structurally diverse groove binders, a structure-based virtual screening campaign has been performed using the X-ray structure of the [d(TGGGGT)](4) quadruplex. Remarkable results were achieved, and six brand new different molecular entities have been found to interact with the groove through NMR experiments. The reported results will certainly stimulate further studies aimed at the design and optimization of new quadruplex-specific groove binders to be applied as anticancer agents and for other diseases.
Dipartimento di Chimica Farmaceutica e Tossicologica, Università degli Studi di Napoli Federico II, via D. Montesano 49, I-80131 Napoli, Italy.
Sandro
S
Cosconati
Luciana
L
Marinelli
Roberta
R
Trotta
Ada
A
Virno
Luciano
L
Mayol
Ettore
E
Novellino
Arthur J
AJ
Olson
Antonio
A
Randazzo
D001665:Binding Sites; D004247:DNA / Q000737:chemistry* / Q000187:drug effects; D054856:G-Quadruplexes / Q000187:drug effects; D019906:Nuclear Magnetic Resonance, Biomolecular; D009930:Organic Chemicals / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D009930:Organic Chemicals; D004247:DNA