Integrative network pharmacology and molecular modelling identify taxifolin as a potential modulator of melatonin...

Mood disorders are increasingly recognised as disorders of circadian dysregulation, with sleep abnormalities acting as both risk factors and clinical hallmarks. Despite extensive evidence linking circadian disruption to affective pathology, the precise molecular mechanisms remain incompletely defined. The present study aimed to identify shared genetic determinants of the sleep-circadian-mood axis and to discover natural neuromodulators that stabilise melatonergic signalling. Using an integrative network pharmacology and computational modelling approach, 644 overlapping genes across mood disorders, circadian rhythm, and insomnia were identified and mapped into protein-protein interaction networks. Functional enrichment revealed convergence on neuroinflammatory signalling (IL6, TNF, STAT3), circadian machinery (CLOCK, ARNTL, PER, CRY), and melatonergic signalling. Notably, melatonin receptors emerged as mechanistically coherent and clinically actionable GPCR targets, despite lower cluster scores relative to inflammation-dominant modules. Structure-based virtual screening of ~ 1,50,000 natural compounds against Melatonin 1 receptor identified taxifolin (- 9.527 kcal/mol) and tanshinone IIA (- 9.515 kcal/mol) as top candidates. Molecular dynamics simulations demonstrated that taxifolin formed highly stable protein-ligand complexes, characterised by sustained hydrogen bonding, reduced RMSD/RMSF fluctuations, and favourable interaction energetics. In contrast, tanshinone showed weaker hydrogen bonding, indicating higher ligand mobility. To provide preliminary biological validation, immunocytochemistry analysis was performed to assess the expression of circadian regulators (CLOCK and BMAL1 (ARNTL)) following treatment. Taxifolin modulated circadian protein expression in a manner comparable to melatonin, indicating an effect on cellular circadian signalling pathways. In conclusion, this study provides a systems-level framework linking circadian disruption, neuroinflammation, and mood pathology, while nominating taxifolin as a natural neuromodulator of melatonergic-associated pathways. These findings highlight taxifolin's translational potential as a safer alternative to synthetic melatonergic agents, representing a new direction in neurotherapy for mood disorders.