Inhibitory Potential of Quercetin Derivatives for GSTP-1 Enzyme: Molecular Docking Study of Methoxylated Derivatives

Abstract

Glutathione S-transferases (GSTs) are an important enzyme class involved in detoxification processes. The overactivation of the GSTP-1 isozyme, particularly in cancer cells, leads to the development of resistance to chemotherapy drugs. Therefore, GSTP-1 inhibitors are gaining importance as potential therapeutic targets in cancer treatment. In this study, we aimed to investigate whether quercetin and its derivatives have inhibitory potential on the GSTP-1 enzyme through molecular docking methods. The crystal structure of the GSTP-1 enzyme was obtained from the Protein Data Bank (PDB ID: 2GSS), and molecular docking studies were conducted using the AutoDock Vina 1.2.5 program. Quercetin derivatives and ethacrynic acid were used as ligands, and the binding energies of these compounds to GSTP-1 were calculated, comparing their inhibitory potentials. Additionally, hydrogen bond interactions were examined alongside binding energies. The binding energy of ethacrynic acid was found to be -6.7 kcal/mol, while quercetin had a binding energy of -7.2 kcal/mol, 3-O-methylquercetin -7.3 kcal/mol, 4-O-methylquercetin -7.2 kcal/mol, and 7-O-methylquercetin -7.5 kcal/mol. These results indicate that the strongest inhibitory effect was exhibited by 7-O-methylquercetin. Furthermore, strong hydrogen bond interactions were observed between quercetin derivatives and GSTP-1. These findings suggest that quercetin derivatives have the potential to inhibit the GSTP-1 enzyme and may pave the way for new strategies in cancer treatment.

Keywords

• Cancer
• GSTP-1
• Quercetin
• Molecular docking

GSTP-1 Enzimi İçin Kuersetin Türevlerinin İnhibitör Potansiyeli: Metoksillenmiş Türevlerin Moleküler Docking Çalışması

Abstract

Glutatyon S-transferazlar (GST'ler), detoksifikasyon süreçlerinde rol oynayan önemli bir enzim sınıfıdır. Özellikle GSTP-1 izozimlerinin kanser hücrelerindeki aşırı aktivasyonu, bu hücrelerin kemoterapi ilaçlarına karşı direnç geliştirmesine neden olmaktadır. Bu nedenle GSTP-1 inhibitörleri, kanser tedavisinde potansiyel bir terapötik hedef olarak önem kazanmaktadır. Bu çalışmada, kuersetin ve türevlerinin GSTP-1 enzimi üzerinde inhibitör potansiyele sahip olup olmadığını moleküler yerleştirme (docking) yöntemiyle araştırmayı amaçladık. Çalışmada, GSTP-1 enziminin kristal yapısı Protein Veri Bankası'ndan (PDB ID: 2GSS) elde edilmiştir ve moleküler yerleştirme çalışmaları AutoDock Vina 1.2.5 programı kullanılarak gerçekleştirilmiştir. Kuersetin türevleri ve etakrinik asit ligand olarak kullanılmış ve bu bileşiklerin GSTP-1 ile bağlanma enerjileri hesaplanarak inhibitör potansiyelleri karşılaştırılmıştır. Ayrıca, bağlanma enerjilerinin yanı sıra hidrojen bağı etkileşimleri de incelenmiştir. Etakrinik asidin bağlanma enerjisi -6.7 kcal/mol olarak bulunurken, kuersetinin -7.2 kcal/mol, 3-O-metilkuersetinin -7.3 kcal/mol, 4-O-metilkuersetinin -7.2 kcal/mol ve 7-O-metilkuersetinin -7.5 kcal/mol bağlanma enerjilerine sahip olduğu belirlenmiştir. Sonuçlar, en güçlü inhibitör etkinin 7-O-metilkuersetin tarafından gösterildiğini ortaya koymaktadır. Ayrıca, kuersetin türevlerinin GSTP-1 ile güçlü hidrojen bağı etkileşimleri gösterdiği tespit edilmiştir. Bu bulgular, kuersetin türevlerinin GSTP-1 enzimi inhibisyon potansiyeline sahip olduğunu ve kanser tedavisinde yeni stratejilere kapı aralayabileceğini işaret etmektedir.

Keywords

• Kanser
• GSTP-1
• Kuersetin
• Moleküler yerleştirme

Ethical Statement

Yazarlar bu çalışma için etik komite onayının gerekli olmadığını beyan etmektedir.

References

1. 1. Alsharairi, N. A., Quercetin derivatives as potential therapeutic agents: an updated perspective on the treatment of nicotine-induced non-small cell lung cancer. International Journal of Molecular Sciences 2023, 24 (20), 15208.
2. 2. Sul, O.-J., Ra, S. W., Quercetin prevents LPS-induced oxidative stress and inflammation by modulating NOX2/ROS/NF-kB in lung epithelial cells. Molecules 2021, 26 (22), 6949.
3. 3. Milanović, Ž. B., Antonijević, M. R., Amić, A. D., Avdović, E. H., Dimić, D. S., Milenković, D. A., Marković, Z. S., Inhibitory activity of quercetin, its metabolite, and standard antiviral drugs towards enzymes essential for SARS-CoV-2: The role of acid–base equilibria. RSC advances 2021, 11 (5), 2838-2847.
4. 4. Lupo, G., Cambria, M. T., Olivieri, M., Rocco, C., Caporarello, N., Longo, A., Zanghì, G., Salmeri, M., Foti, M. C., Anfuso, C. D., Anti‐angiogenic effect of quercetin and its 8‐methyl pentamethyl ether derivative in human microvascular endothelial cells. Journal of cellular and molecular medicine 2019, 23 (10), 6565-6577.
5. 5. Yang, D., Wang, T., Long, M., Li, P., Quercetin: its main pharmacological activity and potential application in clinical medicine. Oxidative Medicine and Cellular Longevity 2020, 2020 (1), 8825387.
6. 6. Hayes, J. D., Flanagan, J. U., Jowsey, I. R., Glutathione transferases. Annu. Rev. Pharmacol. Toxicol. 2005, 45 (1), 51-88.
7. 7. Ozcan, M., Esendagli, G., Musdal, Y., Canpinar, H., Bacanlı, M., Anlar, H. G., Esendağlı‐Yılmaz, G., Beyramzadeh, M., Aksoy, Y., Dual actions of the antioxidant chlorophyllin, a glutathione transferase P1‐1 inhibitor, in tumorigenesis and tumor progression. Journal of cellular biochemistry 2019, 120 (5), 7045-7055.
8. 8. Ozcan, M., Aydemir, D., Bacanlı, M., Anlar, H. G., Ulusu, N. N., Aksoy, Y., Protective effects of antioxidant chlorophyllin in chemically induced breast cancer model in vivo. Biological trace element research 2021, 199, 4475-4488.

9. 9. Singh, R. R., Reindl, K. M., Glutathione S-transferases in cancer. Antioxidants 2021, 10 (5), 701.
10. 10. van Zanden, J. J., Hamman, O. B., van Iersel, M. L., Boeren, S., Cnubben, N. H., Bello, M. L., Vervoort, J., van Bladeren, P. J., Rietjens, I. M., Inhibition of human glutathione S-transferase P1-1 by the flavonoid quercetin. Chemico-biological interactions 2003, 145 (2), 139-148.
11. 11. Wiegand, H., Boesch-Saadatmandi, C., Regos, I., Treutter, D., Wolffram, S., Rimbach, G., Effects of quercetin and catechin on hepatic glutathione-S transferase (GST), NAD (P) H quinone oxidoreductase 1 (NQO1), and antioxidant enzyme activity levels in rats. Nutrition and cancer 2009, 61 (5), 717-722.
12. 12. Dhanaraj, S., A critical review on quercetin bioflavonoid and its derivatives: scope, synthesis, and biological applications with future prospects. Arabian Journal of Chemistry 2023, 16 (8), 104881.
13. 13. Bhattacharya, K., Mahato, S., Deka, S., Chanu, N. R., Shrivastava, A. K., Khanal, P., Netting into the Sophoretin pool: An approach to trace GSTP1 inhibitors for reversing chemoresistance. Computational Biology and Chemistry 2024, 108, 107981.
14. 14. Das, A., Chalil, S., Nigam, P., Magee, P., Janneh, O., Owusu-Apenten, R., Glutathione transferase-P1-1 binding with naturally occurring ligands: assessment by docking simulations. Journal of Biophysical Chemistry 2011, 2 (4), 401-407.
15. 15. Guneidy, R. A., Zaki, E. R., Saleh, N. S.-e., Shokeer, A., Inhibition of human glutathione transferase by catechin and gossypol: comparative structural analysis by kinetic properties, molecular docking and their efficacy on the viability of human MCF-7 cells. The Journal of Biochemistry 2024, 175 (1), 69-83.
16. 16. Oakley, A. J., Rossjohn, J., Lo Bello, M., Caccuri, A. M., Federici, G., Parker, M. W., The three-dimensional structure of the human Pi class glutathione transferase P1-1 in complex with the inhibitor ethacrynic acid and its glutathione conjugate. Biochemistry 1997, 36 (3), 576-585.
17. 17. Rizvi, S. M. D., Shakil, S., Haneef, M., A simple click by click protocol to perform docking: AutoDock 4.2 made easy for non-bioinformaticians. EXCLI journal 2013, 12, 831.
18. 18. Kim, S., Thiessen, P. A., Bolton, E. E., Chen, J., Fu, G., Gindulyte, A., Han, L., He, J., He, S., Shoemaker, B. A., PubChem substance and compound databases. Nucleic acids research 2016, 44 (D1), D1202-D1213.
19. 19. Trott, O., Olson, A. J., AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. Journal of computational chemistry 2010, 31 (2), 455-461.
20. 20. Morris, G. M., Huey, R., Lindstrom, W., Sanner, M. F., Belew, R. K., Goodsell, D. S., Olson, A. J., AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. Journal of computational chemistry 2009, 30 (16), 2785-2791.
21. 21. Kurata, M., Suzuki, M., Takeda, K., Effects of phenol compounds, glutathione analogues and a diuretic drug on glutathione S-transferase, glutathione reductase and glutathione peroxidase from canine erythrocytes. Comparative Biochemistry and physiology. B, Comparative Biochemistry 1992, 103 (4), 863-867.
22. 22. Zhang, K., Das, N. P., Inhibitory effects of plant polyphenols on rat liver glutathione S-transferases. Biochemical pharmacology 1994, 47 (11), 2063-2068.
23. 23. Oakley, A. J., Lo Bello, M., Mazzetti, A. P., Federici, G., Parker, M. W., The glutathione conjugate of ethacrynic acid can bind to human pi class glutathione transferase P1-1 in two different modes. FEBS Letters 1997, 419 (1), 32-36.
24. 24. Rajesh R, U., Dhanaraj, S., A critical review on quercetin bioflavonoid and its derivatives: Scope, synthesis, and biological applications with future prospects. Arabian Journal of Chemistry 2023, 16 (8), 104881.
25. 25. van Zanden, J. J., Ben Hamman, O., van Iersel, M. L. P. S., Boeren, S., Cnubben, N. H. P., Lo Bello, M., Vervoort, J., van Bladeren, P. J., Rietjens, I. M. C. M., Inhibition of human glutathione S-transferase P1-1 by the flavonoid quercetin. Chem Biol Interact 2003, 145 (2), 139-148.
26. 26. Li, M., Li, H., Lu, L., Fu, J., Ao, H., Han, M., Guo, Y., Zhang, H., Wang, Z., Wang, X., Simple preparation and greatly improved oral bioavailability: The supersaturated drug delivery system of quercetin based on PVP K30. Drug Delivery and Translational Research 2024, 1-14.
27. 27. Rich, G. T., Buchweitz, M., Winterbone, M. S., Kroon, P. A., Wilde, P. J., Towards an understanding of the low bioavailability of quercetin: a study of its interaction with intestinal lipids. Nutrients 2017, 9 (2), 111.