Computational network pharmacology, docking, and 100-ns molecular dynamics indicate methoxylated flavonoids—notably Eupatilin—bind multiple PD-relevant targets (HSP90AA1, MMP9, GSK-3β, AKT1) and modulate PI3K-Akt signaling with favorable predicted ADMET.

Provides a prioritized, drug-like multi-target lead and mechanistic hypotheses in PD that justify targeted in vitro and in vivo validation toward potential disease-modifying therapies.

Current therapy for Parkinson's disease (PD), a neurodegenerative disorder that progresses over time marked by protein aggregation, dopaminergic neuronal death and oxidative stress, only provides symptomatic alleviation. By using an integrative computational strategy that combines molecular dynamics simulations, molecular docking and network pharmacology, this study sought for the investigation of the neuroprotective potential of methoxylated flavonoids (MFs). Drug-likeness and ADMET profiling of ten MFs revealed favorable pharmacokinetics, including good oral bioavailability and low predicted toxicity. Network pharmacology identified 172 putative targets, of which 118 overlapped with PD-associated genes, highlighting the multi-targeted nature of these compounds. Protein-protein interaction analysis revealed important hub proteins like HSP90AA1, MMP9, GSK-3β and AKT1 involved in neurodegeneration, oxidative stress regulation, and apoptotic signaling. Analysis of KEGG and GO pathway enrichment revealed significant modulation of the signaling pathway PI3K-Akt and the cellular elements necessary for neuronal survival and repair. Molecular docking revealed high-affinity interactions of Eupatilin and Norwogonin with key PD targets, particularly HSP90AA1 and MMP9. Molecular dynamics simulations confirmed the Eupatilin-HSP90AA1 complex's stability over a 100 ns period, indicating stable interactions and minimal conformational fluctuations. These findings suggest that methoxylated flavonoids possess multi-target therapeutic potential against PD, contributing to broader goals in public health and mental health by modulating interconnected neuroprotective pathways. However, as the results are predictive in nature, confirming their translational value requires experimental confirmation through in vitro and in vivo research. Study highlights Eupatilin as a potential lead substance for additional pharmacological research aimed at disease modification in Parkinson's disease.