Journal
MOLECULES
Volume 20, Issue 1, Pages 206-223Publisher
MDPI
DOI: 10.3390/molecules20010206
Keywords
DNA; G-quadruplex; h-telo; c-myc; alkaloids; berberine; virtual screening; docking; molecular dynamics
Funding
- Italian Ministry of Education [FIRB-IDEAS RBID082ATK_002, 2009MFRKZ8_002]
- Commissione Europea, Fondo Sociale Europeo e della Regione Calabria
- POR Calabria FSE [1007-2013]
- Interregional Research Center for Food Safety and Health at the Magna Graecia University of Catanzaro [MIUR PON a3_00359]
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Several ligands can bind to the non-canonical G-quadruplex DNA structures thereby stabilizing them. These molecules can act as effective anticancer agents by stabilizing the telomeric regions of DNA or by regulating oncogene expression. In order to better interact with the quartets of G-quadruplex structures, G-binders are generally characterized by a large aromatic core involved in pi-pi stacking. Some natural flexible cyclic molecules from Traditional Chinese Medicine have shown high binding affinity with G-quadruplex, such as berbamine and many other alkaloids. Using the structural information available on G-quadruplex structures, we performed a high throughput in silico screening of commercially available alkaloid derivative databases by means of a structure-based approach based on docking and molecular dynamics simulations against the human telomeric sequence d[AG(3)(T(2)AG(3))(3)] and the c-myc promoter structure. We identified 69 best hits reporting an improved theoretical binding affinity with respect to the active set. Among them, a berberine derivative, already known to remarkably inhibit telomerase activity, was related to a better theoretical affinity versus c-myc.
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