Investigation of the inhibitory effects of the telomere-targeted compounds on glutathione S-transferase P1

Glutathione S-transferase P1 (GSTP1) plays a significant role in cancer progression and chemotherapy resistance, with its overexpression diminishing chemotherapeutic efficacy across various tumor types. This study evaluates the inhibitory effects of 6-thio-2 '-deoxyguanosine (6-thio-dG) and its dimeric form (6-thio-2 '-dG-Dimer) on GSTP1. Enzyme inhibition assays with recombinant human GSTP1, kinetic analysis, molecular docking, and molecular dynamic simulations were employed. Enzymatic assays were performed in 0.1 M phosphate buffer (pH 6.5) at 30 degrees C, containing 1 mM EDTA, 1 mM GSH, and 1 mM CDNB. The compounds 6-thio-dG and its dimer were dissolved in 2.5% DMSO for the experiments. The IC50 values indicated that the dimer exhibited a higher potency (IC50: 0.339 mu M) than the monomer (IC50: 15.14 mu M). Kinetic analysis revealed noncompetitive inhibition with glutathione (Ki: 12.26 mu M) and mixed inhibition with CDNB (Ki: 11.41 mu M) for the monomer, whereas the dimer showed mixed inhibition with glutathione (Ki: 0.972 mu M) and competitive inhibition with CDNB (Ki: 0.723 mu M). Molecular docking confirmed the higher binding affinity of the dimer (binding energy: - 7.9 kcal/mol, Ki: 1.595 mu M) compared to the monomer (binding energy: - 6.2 kcal/mol, Ki: 28.21 mu M). The dimer form of 6-thio-dG shows strong potential to enhance chemotherapeutic efficacy by effectively inhibiting GSTP1 and overcoming drug resistance. Its superior inhibitory properties make it a valuable candidate for targeted cancer therapies.