Ağ Farmakolojisi, Moleküler Yerleştirme ve Dinamiklere Dayalı Strateji ile Melatoninin Timoma Üzerindeki Potansiyel Mekanizmasının Araştırılması

Abstract

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.

Keywords

• ER-alfa
• FOS
• MAPK
• PI3K-AKT
• timik epitelyal tümörler

Network Pharmacology, Molecular Docking and Dynamics-Based Strategy to Explore the Potential Mechanism of Melatonin Against Thymoma

Abstract

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.

Keywords

• ER-alpha
• FOS
• MAPK
• PI3K-AKT

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