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

Molecules

Roberta Rocca¹  Federica Moraca¹  Giosuè Costa¹  Stefano Alcaro¹  Simona Distinto²  Elias Maccioni²  Francesco Ortuso¹  Anna Artese¹  Lucia Parrotta¹  Patricia Valentao³ 

[1] Dipartimento di Scienze della Salute, Università degli Studi “Magna Græcia”, Campus “S. Venuta”, Viale Europa, Germaneto 88100, Catanzaro, Italy; E-Mails:;Dipartimento di Scienze della Vita e dell’Ambiente, Università degli Studi di Cagliari, Via Ospedale 72, Cagliari 09124, Italy; E-Mails:Dipartimento di Scienze della Salute, Università degli Studi “Magna Græcia”, Campus “S. Venuta”, Viale Europa, Germaneto 88100, Catanzaro, Italy;

关键词: DNA;    G-quadruplex;    h-telo;    c-myc;    alkaloids;    berberine;    virtual screening;    docking;    molecular dynamics;   

DOI  :  10.3390/molecules20010206

来源: mdpi

【 摘 要 】

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 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[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, a berberine derivative, already known to remarkably inhibit telomerase activity, was related to a better theoretical affinity versus c-myc.

【 授权许可】

CC BY   
© 2014 by the authors; licensee MDPI, Basel, Switzerland.