Design of potent telomerase inhibitors using ligand-based approaches and molecular dynamics simulations studies

Abstract Telomerase is a well-recognised and a promising target for cancer therapy. In this study, we selected ligand-based approaches to design telomerase inhibitors for the development of potent anticancer agents for future cancer therapy. Till date no telomerase inhibitors have been clinically introduced. To investigate the chemical characteristics required for telomerase inhibitory activity, a ligand-based pharmacophore model of oxadiazole derivatives reported from the available literature was generated using the Schrodinger phase tool. The generated pharmacophore model displayed five features, two hydrophobic and three aromatic rings. This selected pharmacophore hypothesis is validated by screening a dataset of reported oxadiazole derivatives. The pharmacophore model was selected for virtual screening using ZINCPharmer against the ZINC database. The ZINC database molecules with pharmacophoric features similar to the selected pharmacophore model and good fitness score were taken for molecular docking studies. With the pkCSM and SwissADME tools we predicted the pharmacokinetic and toxicity of top ten ZINC database compounds based on docking score, binding interactions and identified two in-silicopotential compounds with good ADME and less toxicity. Then both the hit molecules were exposed to molecular dynamic simulation integrated with MM-PBSA binding free energy calculations using GROMACS tools. The MM-PBSA calculations exhibited that the free binding energy of selected protein-ligand complexes were found stable and stabilized with nonpolar and van der walls free energies. Our study suggests that ZINC82107047 and ZINC8839196 can be used as hit molecules for future biological screening and for discovery of safe and potent drugs as telomerase inhibitors for cancer therapy.