Structure-Based Virtual Screening of Novel Natural Alkaloid Derivatives as Potential Binders of h-telo and c-myc DNA G-Quadruplex Conformations

Roberta Rocca, Federica Moraca, Giosuè Costa, Stefano Alcaro, Simona Distinto, Elias Maccioni, Francesco Ortuso, Anna Artese, Lucia Parrotta
2014 Molecules  
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 π-π stacking. Some natural flexible cyclic molecules from Traditional Chinese Medicine have shown high binding
more » ... inity 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[AG3(T2AG3)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, OPEN ACCESS Molecules 2015, 20 207 a berberine derivative, already known to remarkably inhibit telomerase activity, was related to a better theoretical affinity versus c-myc.
doi:10.3390/molecules20010206 pmid:25547724 fatcat:jfnf2go37zbi5cm3w5bost2ram