Multi-Targets Neuroprotective Mechanisms of Phenolic Compounds from Antiaris Africana against Parkinson's Disease

This study presents a mechanistic exploration of the neuroprotective potential of phenolic compounds isolated from Antiaris africana, using an integrative systems pharmacology approach. By mapping phytochemicals to Parkinson’s disease (PD)-associated targets, the research reveals how small molecules such as rutin, isoquercitrin, and ellagic acid engage and modulate multiple disease-relevant proteins. Central to the analysis is the identification of six hub proteins-AKT1, TP53, EGFR, ESR1, SRC, and CASP3-through protein-protein interaction networks and pathway enrichment, indicating their role in apoptosis, kinase signaling, and neuroinflammation. Molecular docking revealed high-affinity interactions, particularly between isoquercitrin and AKT1, and between rutin and several kinases and transcription factors. The application of molecular dynamics simulations demonstrated that ligand binding reduces protein flexibility, enhances compactness, and stabilizes hydrogen-bonding networks. Energetic analyses using MM/GBSA confirmed strong binding profiles, while principal component analysis and dynamic cross-correlation matrices illustrated ligand-induced conformational shifts toward less dynamic, more functionally stable protein states. Importantly, the study moves beyond simple target identification to propose that phenolic compounds from A. africana may act as conformational stabilizers, preventing misfolding and dysfunctional signaling. This hypothesis offers a new dimension to our understanding of natural product neuroprotection in PD, proposing that structure-based stabilization of key proteins may complement traditional antioxidant and anti-apoptotic effects. The findings underscore the therapeutic promise of A. africana in neurodegenerative disease contexts and lay a computational foundation for future experimental validation.