Amentoflavone as a potential telomeric G-Quadruplex DNA stabilizing agent

Abstract

Telomerase enzyme plays a pivotal role in the maintenance of telomere length and thereby increases the longevity of cancer cells. The ability of telomeric DNA sequences to form quadruplex has been identified as potential drug targets for the treatment of various cancers by interfering telomerase activity. The formation of quadruplex has diverse structural conformations and is subjected to detailed DNA-Ligand interaction studies. In the present study, we investigate the possibility of stabilizing parallel quadruplex DNA sequence d [AGGG(TTAGGG)3] at the telomeric end region with the phytochemicals present in the medicinal plant Biophytum sensitivum L. Molecular docking studies reveal that the amentoflavone, a biflavonoid present in the plant binds to the quadruplex DNA and thereby stabilizing the structure. ADMET properties of amentoflavone were also investigated to understand its pharmacokinetics and pharmacological effects. Quadruplex DNA structures are seen to be stabilized in-vitro using cations K+ or Na+. This was further confirmed using molecular dynamics simulation studies of quadruplex DNA structure with K+ and Na+ along with amentoflavone. Though K+ and Na+ orient themselves in the center of the planar structure, amentoflavone binds to the quadruplex DNA structure and thereby stabilizing it. These results show that amentoflavone can stabilize the quadruplex DNA structure as good as the monovalent cations do in-vitro. Hence it is proposed that amentoflavone could be developed as a potent inhibitor of telomerase activity in cancer cells.