Interaction of GHK Tripeptide with Receptors Targeted in Some Cancer Studies: A Theoretical Approach with Molecular Docking

Abstract

Cancer, defined as the uncontrolled growth and proliferation of cells, is a serious disease seen in many people around the world. For this reason, a lot of work has been done and continues to be done by scientists for the diagnosis and treatment of cancer. It is known that various receptors are targeted in studies on cancers. In this study, ER, PR, EGFR and HER2 receptors, which are among the most frequently used target receptors, were selected. GHK is a tripeptide that has important benefits such as increasing cancer resistance and reversing cancer cells. In this study, the complex structures formed by the most commonly used target receptors (ER, PR, EGFR and HER2) and the GHK tripeptide were examined. These complex structures were obtained by molecular docking method that is a molecular modeling method used to predict how a receptor interacts with small molecules. As a result of the study, binding affinities, close interactions, and interaction types of GHK and receptors were determined, and interaction profiles with various drugs (such as tamoxifen, erlotinib and neratinib) in the literature were examined comparatively. In the light of the findings obtained in the studies, it was determined that the GHK tripeptide gave similar interaction profiles with the drugs used in cancer treatment.

Keywords

• Peptide
• GHK
• EGFR
• Cancer
• Docking

References

1. 1. D’arcy MS. Cell death: a review of the major forms of apoptosis, necrosis and autophagy. Cell biology international. 2019;43(6):582- 92.
2. 2. Acharya R, Chacko S, Bose P, Lapenna A, Pattanayak SP. Structure based multitargeted molecular docking analysis of selected furanocoumarins against breast cancer. Scientific reports. 2019;9(1):1-13.
3. 3. Holst F, Stahl PR, Ruiz C, Hellwinkel O, Jehan Z, Wendland M, et al. Estrogen receptor alpha (ESR1) gene amplification is frequent in breast cancer. Nature genetics. 2007;39(5):655-60.
4. 4. Fowler AM, Alarid ET. Amping up estrogen receptors in breast cancer. Breast Cancer Research. 2007;9:1-3.
5. 5. Lange CA, Yee D. Progesterone and breast cancer. Women’s Health. 2008;4(2):151-62.
6. 6. Swargiary G, Mani S. ER and PGR targeting ability of phytocompounds derived from Centella asiatica and Andrographis paniculata: an in-silico approach. Journal of Herbal Medicine. 2022;32:100541.
7. 7. Dhiani BA, Nurulita NA, Fitriyani F. Protein-protein Docking Studies of Estrogen Receptor Alpha and TRIM56 Interaction for Breast Cancer Drug Screening. Indonesian Journal of Cancer Chemoprevention. 2022;13(1):46-54.
8. 8. Nilsson S, Gustafsson JÅ. Estrogen receptors: therapies targeted to receptor subtypes. Clinical Pharmacology & Therapeutics. 2011;89(1):44-55.

9. 9. Mani S, Swargiary G, Gulati S, Gupta S, Jindal D. Molecular docking and ADMET studies to predict the anti-breast cancer effect of aloin by targeting estrogen and progesterone receptors. Materials Today: Proceedings. 2021.
10. 10. Saghiri K, Daoud I, Melkemi N, Mesli F. QSAR study, molecular docking/dynamics simulations and ADME prediction of 2-phenyl- 1H-indole derivatives as potential breast cancer inhibitors. Biointerface Res Appl Chem. 2022;13(2):154.
11. 11. Sing LC, Roy A, Hui LY, Mun CS, Rajak H, Karunakaran R, et al. Multi-targeted molecular docking, drug-likeness and ADMET studies of derivatives of few quinoline-and acridine-based FDA-approved drugs for anti-breast cancer activity. Structural Chemistry. 2022;33(3):649-69.
12. 12. Prabhavathi H, Dasegowda K, Renukananda K, Karunakar P, Lingaraju K, Raja Naika H. Molecular docking and dynamic simulation to identify potential phytocompound inhibitors for EGFR and HER2 as anti-breast cancer agents. Journal of Biomolecular Structure and Dynamics. 2022;40(10):4713-24.
13. 13. Costa R, Shah AN, Santa-Maria CA, Cruz MR, Mahalingam D, Carneiro BA, et al. Targeting Epidermal Growth Factor Receptor in triple negative breast cancer: New discoveries and practical insights for drug development. Cancer treatment reviews. 2017;53:111-9.
14. 14. Mueller KL, Yang Z-Q, Haddad R, Ethier SP, Boerner JL. EGFR/ Met association regulates EGFR TKI resistance in breast cancer. Journal of molecular signaling. 2010;5(1):1-8.
15. 15. da Cunha Santos G, Shepherd FA, Tsao MS. EGFR mutations and lung cancer. Annual Review of Pathology: Mechanisms of Disease. 2011;6:49-69.
16. 16. de Castro-Carpeño J, Belda-Iniesta C, Sáenz EC, Agudo EH, Batlle JF, Barón MG. EGFR and colon cancer: a clinical view. Clinical and Translational Oncology. 2008;10:6-13.
17. 17. Iqbal N, Iqbal N. Human epidermal growth factor receptor 2 (HER2) in cancers: overexpression and therapeutic implications. Molecular biology international. 2014;2014.
18. 18. Tripathi S, Srivastava G, Sharma A. Computational Design of Multi-Target Drugs Against Breast Cancer. Multi-Target Drug Design Using Chem-Bioinformatic Approaches. 2019:443-58.
19. 19. Landi L, Cappuzzo F. HER2 and lung cancer. Expert review of anticancer therapy. 2013;13(10):1219-28.
20. 20. Mar N, Vredenburgh JJ, Wasser JS. Targeting HER2 in the treatment of non-small cell lung cancer. Lung Cancer. 2015;87(3):220-5.
21. 21. Budama-Kilinc Y, Kecel-Gunduz S, Cakir-Koc R, Aslan B, Bicak B, Kokcu Y, et al. Structural characterization and drug delivery system of natural growth-modulating peptide against glioblastoma cancer. International Journal of Peptide Research and Therapeutics. 2021;27(3):2015-28.
22. 22. Kokcu Y, Kecel-Gunduz S, Budama-Kilinc Y, Cakir-Koc R, Bicak B, Zorlu T, et al. Structural analysis, molecular dynamics and docking calculations of skin protective tripeptide and design, characterization, cytotoxicity studies of its PLGA nanoparticles. Journal of Molecular Structure. 2020;1200:127046.
23. 23. Pickart L, Vasquez-Soltero JM, Pickart FD, Majnarich J. GHK, the human skin remodeling peptide, induces anti-cancer expression of numerous caspase, growth regulatory, and DNA repair genes. Journal of Analytical Oncology. 2014;3(2):79-87.
24. 24. Hong Y, Downey T, Eu KW, Koh PK, Cheah PY. A ‘metastasisprone’signature for early-stage mismatch-repair proficient sporadic colorectal cancer patients and its implications for possible therapeutics. Clinical & experimental metastasis. 2010;27:83-90.
25. 25. Lamb J, Crawford ED, Peck D, Modell JW, Blat IC, Wrobel MJ, et al. The Connectivity Map: using gene-expression signatures to connect small molecules, genes, and disease. science. 2006;313(5795):1929- 35.
26. 26. Pickart L, Margolina A. Modulation of Gene Expression in Human Breast Cancer MCF7 and Prostate Cancer PC3 Cells by the Human Copper-Binding Peptide GHK-Cu. OBM Genetics. 2021;5(2):1-18.
27. 27. Matalka L, Ford A, Unlap M. The tripeptide, GHK, induces programmed cell death in SH-SY5Y neuroblastoma cells. Journal of Biotechnology & Biomaterials. 2012;2:1-4.
28. 28. Pickart L, Vasquez-Soltero JM, Margolina A. GHK and DNA: resetting the human genome to health. BioMed research international. 2014;2014.
29. 29. Bicak B, Gunduz SK. Computer-Aided Drug Design of Plant- Based Compounds. Isolation, Characterization, and Therapeutic Applications of Natural Bioactive Compounds: IGI Global; 2022. p. 320-45.
30. 30. Gunduz SK, Bicak B, Ozel AE. Advancements in cancer therapeutics: Computational drug design methods used in cancer studies. Handbook of research on advancements in cancer therapeutics: IGI Global; 2021. p. 89-115.
31. 31. Tanenbaum DM, Wang Y, Williams SP, Sigler PB. Crystallographic comparison of the estrogen and progesterone receptor’s ligand binding domains. Proceedings of the National Academy of Sciences. 1998;95(11):5998-6003.
32. 32. Madauss KP, Grygielko ET, Deng S-J, Sulpizio AC, Stanley TB, Wu C, et al. A structural and in vitro characterization of asoprisnil: a selective progesterone receptor modulator. Molecular endocrinology. 2007;21(5):1066-81.
33. 33. Stamos J, Sliwkowski MX, Eigenbrot C. Structure of the epidermal growth factor receptor kinase domain alone and in complex with a 4-anilinoquinazoline inhibitor. Journal of biological chemistry. 2002;277(48):46265-72.
34. 34. Ishikawa T, Seto M, Banno H, Kawakita Y, Oorui M, Taniguchi T, et al. Design and synthesis of novel human epidermal growth factor receptor 2 (HER2)/epidermal growth factor receptor (EGFR) dual inhibitors bearing a pyrrolo [3, 2-d] pyrimidine scaffold. Journal of medicinal chemistry. 2011;54(23):8030-50.
35. 35. Trott O, Olson AJ. 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):455-61.
36. 36. DeLano WL. Pymol: An open-source molecular graphics tool. CCP4 Newsl Protein Crystallogr. 2002;40(1):82-92.
37. 37. Biovia DS. Discovery studio modeling environment. Release; 2017.
38. 38. Mustarichiei R, Levitas J, Arpina J. In silico study of curcumol, curcumenol, isocurcumenol, and β-sitosterol as potential inhibitors of estrogen receptor alpha of breast cancer. Medical Journal of Indonesia. 2014;23(1):15-24.
39. 39. Liu Y, Ma H, Yao J. ERα, a key target for cancer therapy: A review. OncoTargets and therapy. 2020;13:2183.
40. 40. Ariazi EA, Leitao A, Oprea TI, Chen B, Louis T, Bertucci AM, et al. Exemestane's 17-hydroxylated metabolite exerts biological effects as an androgen. Molecular cancer therapeutics. 2007;6(11):2817-27.
41. 41. Li Z, Wei H, Li S, Wu P, Mao X. The role of progesterone receptors in breast cancer. Drug Design, Development and Therapy. 2022:305- 14.
42. 42. Pratama MRF, Poerwono H, Siswandono S. Design and molecular docking of novel 5-O-Benzoylpinostrobin derivatives as anti-breast cancer. Thai Journal of Pharmaceutical Sciences (TJPS). 2020;43(4).
43. 43. Kesuma D, Siswandono S, Kirtishanti A. Molecular Docking And Biological Activity Of N-(4-Methoxy)-Benzoyl-N’-Phenylthiourea And N-(4-Trifluoro)-Benzoyl-N’-Phenylthiourea As Antibreast Cancer Candidates. Rasayan Journal of Chemistry. 2022;15(2):1503- 8.
44. 44. Garcia-Closas M, Brinton L, Lissowska J, Chatterjee N, Peplonska B, Anderson W, et al. Established breast cancer risk factors by clinically important tumour characteristics. British journal of cancer. 2006;95(1):123-9.
45. 45. Miše I, Vučić M, Maričević I, Šokčević M, Čurić-Jurić S. Histologic subtypes of invasive lobular carcinoma in correlation with tumor status and hormone receptors. Acta Clinica Croatica. 2010;49(3):275-81.
46. 46. Özmen V. Türkiye'de Meme Kanseri: Klinik ve Histopatolojik Özellikler (13.240 Olgunun Analizi). Meme Sagligi Dergisi/Journal of Breast Health. 2014;10(2).