Network pharmacology and structure-based analysis of Baicalein, berberine, and rosmarinic acid as multi-gene modulators of neuroinflammation and apoptosis in syringomyelia
ABSTRACT Syringomyelia is a progressive neurological disorder characterized by spinal cord cavitation, neuroinflammation, extracellular matrix dysregulation, and apoptosis. Genetic and molecular studies implicate multiple signaling pathways and protein targets, yet current therapies remain inadequate. To identify phytochemical candidates capable of modulating key genetic and protein targets implicated in syringomyelia using an integrative network pharmacology and molecular modeling strategy. Network pharmacology analysis identified five hub proteins—MMP9, CASP3, TNF, PPARG, and ESR1—associated with syringomyelia pathophysiology. Baicalein, berberine, and rosmarinic acid were selected based on reported anti-inflammatory, neuroprotective, antioxidant, and anti-apoptotic effects. Molecular docking, molecular dynamics simulations, MM/GBSA binding free energy estimations, and interaction profiling were employed to assess multi-target binding potential and stability. Baicalein exhibited the most robust multi-target binding, particularly to MMP9 (−40.9 kcal/mol) and PPARG (−34.8 kcal/mol), via aromatic and hydrophobic interactions. Rosmarinic acid showed strong polar contacts with CASP3 (−27.6 kcal/mol), while berberine demonstrated moderate but less consistent target engagement. Interaction mapping and surface analyses supported the molecular complementarity between ligands and targets. Baicalein and rosmarinic acid emerge as promising multi-target modulators for syringomyelia, with the potential to influence neuroinflammation, matrix remodeling, and apoptotic pathways.