Study On The Pharmacophore Model Of Telomeric G - Quadruplex Ligand

G-rich DNA sequences, in some particular situation, are capable of forming special DNA secondary structures, which are called G-quadruplex. It exists in many important parts of human, such as telomeres in the end of chromosomes and promoter regions of many oncogenes. In cancer cells and immortalized cell lines, telomerases show their activity to play a role in lengthening telomeres. But the presence of G-quadruplex inhibits the activity of telomerase, which gradually shortens the telomeres in the process of cell division and eventually leads to programmed cell death. Design of the anti-cancer drugs targeted in G-quadruplex has become a very important means currently. This article built 3D-pharmacophore models based on G-quadruplex ligands and receptors, and the complexes of its ligands and receptors and checked the validities of these models by using active and inactive ligands. Then, we used the obtained models to perform virtual screening of high flux in the Dictionary of Natural Products. We first used the methods of rapid molecular docking and half of the flexible docking; then with the semi flexible accurate molecular docking technology, we theoretically confirmed the ligand compounds of G-quadruplex.The main research contents and results of this paper are as follows:We built 3D-pharmacophore models based on G-quadruplex ligands, G-quadruplex receptors, and the complexes of its ligands and receptors respectively and checked the validities of these models by using active and inactive ligands. Eventually, we chose the best one of each type for the next step.Next, we used the three models to perform virtual screening of high flux in the Dictionary of Natural Products and got 3600 compounds. Most results were filtered out according to the Linpiski’s rules of five and Veber’s rule and 377,359,362 compounds remained respectively. These remained ones have the possibility to be medicine.In consideration of the fact that there were still many compounds remained, we took semi-flexible docking firstly and screened out 270, 208 and 256 compounds for three models respectively. Then, we made consistency evaluation for each model’s top 50 compounds ranked by scores using the semi-flexible docking, and selected 5 optimal compounds based on the scores and common to these three models. They are Cimiracemate B, Cimiracemate C, Cimiracemate D, Anticancer Stilbenolignan PMV70P691-042, Anticancer Flavonoid PMV70P691-97. Finally, we made the molecular docking for the 5 compounds above and analyzed the results by semi flexible accurate molecular docking technology. And we eventually confirmed these 5 compounds can be used as ligands to telomere G-quadruplex, which provided theoretical basis for research and development of new medicines against cancer.