What question did this study set out to answer?

The aim is to investigate the anti-cancer mechanisms of melatonin against thymic epithelial tumors.

May 3, 2026Open Access

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

EAEmel AkbabaKırıkkale University ZDZekeriya DüzgünGiresun University

Key Points

The aim is to investigate the anti-cancer mechanisms of melatonin against thymic epithelial tumors.
Identified melatonin and thymoma-related proteins from databases, focusing on 2160 genes.
Constructed a protein-protein interaction network using STRING and analyzed hub genes via Cytoscape.
Performed KEGG pathway analysis and molecular docking with dynamics simulations.
Molecular docking showed ESR1 had the lowest binding enthalpy (-100.36 kJ/mol) during MD simulations, indicating stability.
KEGG analysis highlighted pathways such as PI3K-AKT, MAPK, and FOXO impacted by melatonin.
Melatonin interactions with several proteins suggest broader regulatory effects on tumor survival pathways.

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.

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