ahi evran med j Ahi Evran Medical Journal 2619-9203 Kirsehir Ahi Evran University 10.46332/aemj.1666706 Clinical Chemistry Clinical Oncology Klinik Kimya Klinik Onkoloji Ağ Farmakolojisi, Moleküler Yerleştirme ve Dinamiklere Dayalı Strateji ile Melatoninin Timoma Üzerindeki Potansiyel Mekanizmasının Araştırılması Network Pharmacology, Molecular Docking and Dynamics-Based Strategy to Explore the Potential Mechanism of Melatonin Against Thymoma https://orcid.org/0000-0003-4915-5153 Akbaba Emel KIRIKKALE ÜNİVERSİTESİ, TIP FAKÜLTESİ https://orcid.org/0000-0001-6420-6292 Düzgün Zekeriya GİRESUN ÜNİVERSİTESİ 04 29 2026 10 1 120 132 03 27 2025 01 30 2026 Copyright © 2017, Ahi Evran Medical Journal 2017 Ahi Evran Medical Journal

Amaç: Timik epitelyal tümörler, nadir görülen neoplazmlar olmalarına rağmen, ön mediastinumun en yaygın tümörleridir. Genel-likle cerrahi ile tedavi edilirler,ancak, kemoterapi de gerektirebilirler. Sirkadiyen ritimleri düzenlemesiyle bilinen melatonin, çeşitli malignitelere karşı anti-kanser özellikler göstermiştir. Ancak, timik epitelyal tümörler üzerindeki etkileri henüz araştırılmamıştır.Araçlar ve Yöntem: Melatonin ve timoma ile ilişkili proteinler (toplamda 2170 gen) çeşitli veri tabanlarında taranmıştır. Daha sonra, kesişen genlerin (316 gen) protein-protein etkileşim ağı STRING veri tabanı kullanılarak oluşturulmuştur. Melatonin ve timoma arasındaki hub genleri belirlemek için Cytoscape kullanılmıştır. Bulgular: KEGG yolak analizi, ilişkili yolakların PI3K-AKT, MAPK, HIF-1 ve FOXO olduğunu ortaya koymuştur. Moleküler yerleştirme ve dinamik simülasyonları, melatonin ile hub genler, özellikle ESR1 (ER-alfa) ve FOS arasında yüksek konformasyo-nel stabilite olduğunu göstermiş olup, tümör baskılanmasında potansiyel düzenleyici roller sergilemiştir. ESR1, başlangıç yerleş-tirme skorlarından farklı olarak, en düşük MMPBSA bağlanma entalpisi (-100.36 kJ/mol, 100-ns MD simülasyonlarından) gös-termiştir. TP53 en düşük yerleştirme bağlanma serbest enerjisi (-11.49 kcal/mol) göstermesine rağmen, ESR1, MD yörüngesi boyunca üstün konformasyonel stabilite ve entalpik uygunluk sergilemiş olup, östrojen reseptörü aracılı transkripsiyonel aktivite-nin düzenlenmesinde kritik bir rol oynayabileceğini düşündürmektedir. ESR1/melatonin kompleksi arasındaki yüksek konformas-yonel stabilite, östrojen reseptör-α aktivitesini modüle edebilir ve muhtemelen PI3K/AKT ve MAPK yolaklarını düzenleyerek kanser hücre büyümesini ve ilerlemesini engelleyebilir. Ek olarak, melatoninin p53, SMAD3, MYC ve STAT3 ile etkileşimleri, tümör hücrelerinin düzenlenmesi ve hayatta kalma yolakları üzerinde daha geniş bir etki alanına sahip olabileceğini göstermektedir.Sonuç: Bu bulgular, melatoninin timoma ve ilgili kanser türleri üzerindeki anti-kanser etkilerinin moleküler mekanizmalarına dair yeni bilgiler sunarak hedefe yönelik terapötik müdahaleler için potansiyel bir yol açmaktadır.

Purpose: Thymic epithelial tumors, although rare neoplasms, are the most common tumors of the anterior mediastinum. They are generally treated with surgery; however, they may also require chemotherapy. Melatonin, known for regulating circadian rhythms, has demonstrated anti-cancer properties However, its effects on thymic epithelial tumors have not yet been investigated.Materials and Methods: Melatonin and thymoma-related proteins (2170 genes) were screened from various databases. Then, protein-protein interaction network of the intersected genes (316 genes) was constructed using STRING database. Cytoscape was utilized to determine hub genes .Results: KEGG analysis revealed the associated pathways as PI3K-AKT, MAPK, HIF-1, and FOXO. Molecular docking and dy-namics simulations revealed high conformational stability between melatonin and hub genes, notably ESR1 (ER-alpha) and FOS. ESR1 exhibited the lowest MMPBSA binding enthalpy (-100.36 kJ/mol from 100-ns MD simulations), which is distinct from the initial docking scores. Although TP53 showed the lowest docking binding free energy (-11.49 kcal/mol), ESR1 demonstrated superior conformational stability and enthalpic favorability throughout the MD trajectory, suggesting a critical role in modulating estrogen receptor-mediated transcriptional activity. The high conformational stability in ESR1/melatonin complex could modulate the activity of estrogen receptor-α and probably inhibit cancer cell growth and progression through the regulation of PI3K/AKT and MAPK pathways. Additionally, melatonin interactions with p53, SMAD3, MYC, and STAT3 suggest a broader impact on tumor cell regulation and survival pathways. Conclusion: These findings provide novel insights into the molecular mechanisms underlying melatonin’s anti-cancer effects on thymoma and related cancer types, offering a potential avenue for targeted therapeutic interventions.

 ER-alpha FOS MAPK PI3K-AKT ER-alfa FOS MAPK PI3K-AKT timik epitelyal tümörler 1. Savino W, Lepletier A. Thymus-derived hormonal and cellular control of cancer. Front Endocrinol. 2023;14:1168186. doi:10.3389/fendo.2023.1168186 2. Scorsetti M, Leo F, Trama A, et al. Thymoma and thymic carcinomas. Crit Rev Oncol Hematol 2016;99:332-350. doi:10.1016/j.critrevonc.2016.01.012 3. Muto Y, Okuma Y. Therapeutic options in thymomas and thymic carcinomas. Expert Rev Anticancer Ther. 2022;22(4):401-413. doi:10.1080/14737140.2022.2052278 4. Berghmans T, Durieux V, Holbrechts S, et al. Systemic treatments for thymoma and thymic carcinoma: A systematic review. Lung Cancer. 2018;126:25-31. doi:10.1016/j.lungcan.2018.10.018 5. Talib WH, Alsayed AR, Abuawad A, et al. Melatonin in cancer treatment: Current knowledge and future opportunities. Molecules. 2021;26(9):2506. doi:10.3390/molecules26092506 6. Li Y, Li S, Zhou Y, et al. Melatonin for the prevention and treatment of cancer. Oncotarget. 2017;8(24): 39896–39921. doi:10.18632/oncotarget.16379 7. Wang L, Wang C, Choi WS. Use of melatonin in cancer treatment: where are we? Int J Mol Sci. 2022;23(7)3779. doi:10.3390/ijms23073779 8. Samanta S. Melatonin: an endogenous miraculous indolamine, fights against cancer progression. J Cancer Res Clin Oncol. 2020;146(8):1893-1922. doi:10.1007/s00432-020-03292-w 9. Bhattacharya S, Patel KK, Dehari D, Agrawal AK, Singh S. Melatonin and its ubiquitous anticancer effects. Mol Cell Biochem. 2019;462(1-2):133-155. doi:10.1007/s11010-019-03617-5 10. Bondy SC, Campbell A. Melatonin and regulation of immune function: impact on numerous diseases. Curr Aging Sci. 2020;13(2):92-101. doi:10.2174/1874609813666200711153223 11. Ahmad SB, Ali A, Bilal M, et al. Melatonin and health: insights of melatonin action, biological functions, and associated disorders. Cell Mol Neurobiol. 2023;43(6):2437-2458. doi:10.1007/s10571-023-01324-w 12. Shaker B, Ahmad S, Lee J, et al. In silico methods and tools for drug discovery. Comput Biol Med. 2021;137:104851. doi:10.1016/j.compbiomed.2021.104851 13. Wu X, Xu LY, Li EM, Dong G. Application of molecular dynamics simulation in biomedicine. Chem Biol Drug Des. 2022;99(5):789-800. doi:10.1111/cbdd.14038 14. Knox C, Law V, Jewison T, et al. DrugBank 3.0: a comprehensive resource for 'Omics' research on drugs. Nucleic Acids Res. 2011;39:D1035-D1041. doi:10.1093/nar/gkq1126 15. Nickel J, Gohlke BO, Erehman J, et al. SuperPred: update on drug classification and target prediction. Nucleic Acids Res. 2014;42:W26-31. doi:10.1093/nar/gku477 16. Piñero J, Ramírez-Anguita JM, Saüch-Pitarch J, et al. The DisGeNET knowledge platform for disease genomics: 2019 update. Nucleic Acids Res. 2020;48(D1):D845-D855. doi:10.1093/nar/gkz1021 17. Chin CH, Chen SH, Wu HH, et al. CytoHubba: identifying hub objects and sub-networks from complex interactome. BMC Syst Biol. 2014;8 Suppl 4:S11. doi:10.1186/1752-0509-8-S4-S1 18. Morris GM, Huey R, Lindstrom W, et al. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J Comput Chem. 2009;30(16):2785-2791. doi:10.1002/jcc.21256 19. Sousa da Silva AW, Vranken WF. ACPYPE-Antechamber python parser interface. BMC res notes. 2012;5:1-8. doi:10.1186/1756-0500-5-367 20. Jakalian A, Bush BL, Jack DB, Bayly CI. Fast, efficient generation of high‐quality atomic charges. AM1‐BCC model: I. Method. J Comput Chem. 2000;21(2):132-146. doi:10.1002/(SICI)1096-987X(20000130)21:2<132::AID-JCC5>3.0.CO;2-P 21. Abraham MJ, Murtola T, Schulz R, et al. GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX. 2015;1:19-25. doi:10.1016/j.softx.2015.06.001 22. Lindorff‐Larsen K, Piana S, Palmo K, et al. Improved side‐chain torsion potentials for the Amber ff99SB protein force field. Proteins. 2010;78(8):1950-1958. doi:10.1002/prot.22711 23. Mark P, Nilsson L. Structure and dynamics of the TIP3P, SPC, and SPC/E water models at 298 K. J Phys Chem. A 2001;105(43):9954-9960. doi:10.1021/jp003020w 24. Hess B, Bekker H, Berendsen HJ, Fraaije JG. LINCS: A linear constraint solver for molecular simulations. J Comput Chem. 1997;18(12):1463-1472. doi:10.1002/(SICI)1096-987X(199709)18:12<1463::AID-JCC4>3.0.CO;2-H 25. Berendsen HJ, Postma Jv, Van Gunsteren WF, et al. Molecular dynamics with coupling to an external bath. J Chem Phys. 1984;81(8):3684-3690. doi:10.1063/1.448118 26. Martoňák R, Laio A, Parrinello M. Predicting crystal structures: the Parrinello-Rahman method revisited. Phys Rev Lett. 2003;90(7):075503. doi:10.1103/PhysRevLett.90.075503 27. Morgos DT, Stefani C, Miricescu D, et al. Targeting PI3K/AKT/mTOR and MAPK signaling pathways in gastric cancer. Int J Mol Sci. 2024;25(3). doi:10.3390/ijms25031848 28. Lee SH, Golinska M, Griffiths JR. HIF-1-Independent mechanisms regulating metabolic adaptation in hypoxic cancer cells. Cells. 2021;10(9):2371. doi:10.3390/cells10092371 29. Farhan M, Wang HT, Gaur U, et al. FOXO signaling pathways as therapeutic targets in cancer. Int J Biol Sci. 2017;13(7):815-827. 30. Akbaba E. Molecular mechanisms of melatonin for treating medullary thyroid cancer using analysis. Adv Pharmacol Pharm. 2024;12(4):430-442. doi:10.7150/ijbs.20052 31. Arao Y, Korach KS. The physiological role of estrogen receptor functional domains. Essays Biochem. 2021;65(6):867-875. doi:10.1042/EBC20200167 32. Furth PA, Wang W, Kang K, et al. Esr1 but Not CYP19A1 Overexpression in mammary epithelial cells during reproductive senescence induces pregnancy-like proliferative mammary disease responsive to anti-hormonals. Am J Pathol. 2023;193(1):84-102. doi:10.1016/j.ajpath.2022.09.007 33. Khatpe AS, Adebayo AK, Herodotou CA, et al. Nexus between PI3K/AKT and estrogen receptor signaling in breast cancer. Cancers. 2021;13(3):369. doi:10.3390/cancers13030369 34. Goyal R, Gupta T, Bal A, et al. Role of melatonin in breast carcinoma: correlation of expression patterns of melatonin-1 receptor with estrogen, progesterone, and HER2 receptors. Appl Immunohistochem Mol Morphol. 2020;28(7):518-523. doi:10.1097/PAI.0000000000000788 35. Lopes J, Arnosti D, Trosko JE, et al. Melatonin decreases estrogen receptor binding to estrogen response elements sites on the OCT4 gene in human breast cancer stem cells. Genes Cancer. 2016;7(5-6):209-217. doi:10.18632/genesandcancer.107 36. Hill SM, Belancio VP, Dauchy RT, et al. Melatonin: an inhibitor of breast cancer. Endocr Relat Cancer 2015;22(3):R183-204. doi:10.1530/ERC-15-0030 37. Marvalim C, Datta A, Lee SC. Role of p53 in breast cancer progression: An insight into p53 targeted therapy. Theranostics. 2023;13(4):1421-1442. doi:10.7150/thno.81847 38. Jeon HY, Pornour M, Ryu H, et al. SMAD3 promotes expression and activity of the androgen receptor in prostate cancer. Nucleic Acids Res. 2023;51(6):2655-2670. doi:10.1093/nar/gkad043