Integrative Network Pharmacology, Molecular Docking, and Dynamics Simulation Guided Discovery of Anethole, Carvacrol, Carnosol, Nicotine, and Paeonol as Potential Therapeutics for Parkinson's Disease.

Parkinson's disease (PD), a prevalent, debilitating neurodegenerative disorder, severely impacts patient well-being and imposes a significant societal burden. Current therapies, such as L-DOPA, MAO-B inhibitors, dopamine agonists, and anticholinergics, offer only temporary symptomatic relief and fail to modify disease progression, underscoring the need for safer, more effective treatment strategies. This study aims to evaluate the neuroprotective potential of nine medicinal plants, which have established anti-parkinsonian effects in preclinical models. To achieve this, a network pharmacology approach was used on an in-house database of 1221 constituents to uncover their potential therapeutic mechanisms in PD. The analysis identified 45 constituents interacting with 60 PD targets, including key compounds such as anethole, carvacrol, carnosol, nicotine, and paeonol, which modulate multiple PD-associated genes. Moreover, enrichment analyses conducted utilizing the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) databases revealed significant pathway and biological process enrichment, indicating a possible synergistic interaction among these constituents. In particular, these analyses highlighted that the constituents might influence critical pathways, including the hypoxia-inducible factor-1 signaling pathway, the tumor necrosis factor signaling pathway, and neurodegeneration-related pathways across multiple diseases. Protein-protein interaction analysis identified caspase-3 (CASP3), prostaglandin-endoperoxide synthase-2 (PTGS2/COX2), interleukin-10 (IL-10), and matrix metallopeptidase-9 (MMP9) as hub genes, which are involved in key processes like apoptosis, oxidative stress, autophagy, and neuroinflammation. Additionally, molecular docking, dynamics simulations, and binding free energy calculations demonstrated stable interactions between these constituents and hub targets, indicating their potential to modulate PD pathogenesis. In conclusion, these findings suggest potential therapeutic mechanisms of the identified constituents in PD and may provide a basis for future preclinical and clinical studies to further explore their neuroprotective effects.