ASSESSING THE POTENTIAL OF HYPOXIA-TARGETING AGENTS AS GSTP1 INHIBITORS IN OVERCOMING CANCER DRUG RESISTANCE

Abstract

Objective: The persistent challenge of drug resistance in cancer therapy is closely linked to the detoxification activity of glutathione S-transferase P1 (GSTP1). This study aims to assess the potential of hypoxia-targeting agents as GSTP1 inhibitors to address drug resistance mechanisms in cancer. Material and Methods: Molecular docking simulations were performed using the crystal structure of GSTP1 (PDB ID: 2GSS). Eight hypoxia-targeting agents were tested, including BAY 87-2243, Vadimezan, SLC-0111, Acriflavine, PX-478, Evofosfamide, Bevacizumab, and the reference GSTP1 inhibitor ethacrynic acid. Binding affinities were calculated using AutoDock Vina, and interaction profiles were visualized with Discovery Studio. Results: Among the tested compounds, BAY 87-2243 exhibited the highest binding affinity to GSTP1 with a binding energy of -9.1 kcal/mol, surpassing ethacrynic acid (-6.7 kcal/mol). Vadimezan (-7.9 kcal/mol) and SLC-0111 (-7.2 kcal/mol) also demonstrated strong inhibitory potential. Key interactions included hydrogen bonds with residues GLN A:51 and ARG A:13 and hydrophobic interactions with PHE A:8. Other compounds displayed lower binding affinities, ranging from -6.6 to -5.7 kcal/mol. Conclusion: Hypoxia-targeting agents, particularly BAY 87-2243, Vadimezan, and SLC-0111, show promising GSTP1 inhibition potential, offering dual functionality to modulate tumor hypoxia and counteract drug resistance. These findings warrant further in vitro and in vivo studies to explore their clinical application in cancer therapy.