Targeting the G-quadruplex structure in the hTERT promoter: In silico screening of phytocompounds and replica exchange molecular dynamics simulations.

Abstract

Telomerase activity plays a crucial role in maintaining telomere length and cellular immortality, making it an attractive target for cancer therapy. The human telomerase reverse transcriptase (hTERT) promoter contains a G-rich region that can form G-quadruplex (G4) structures, which have been shown to regulate hTERT expression. In this study, we used in silico screening and molecular dynamics simulations to identify phytocompounds that can stabilize the G4 structure in the hTERT promoter. We performed shape-based and pharmacophore-based screening of a phytochemical database and identified two lead compounds with assistance from oleanolic acid and maslinic acid as controls which showed in vitro telomerase activity. Molecular docking and replica exchange molecular dynamics simulations for a temperature profile of 300K to 350K were used to evaluate the binding affinity and stability of these compounds with two different G4 conformations in the hTERT promoter. Our results suggest that astragaloside-1 can stabilize the parallel-stranded G4 conformation (2kze) in the hTERT promoter, while novel compounds may be required to stabilize the intramolecular G4 conformation (2kzd). Our study highlights the potential of in silico screening and molecular dynamics simulations in identifying lead compounds for targeting G4 structures.