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

Parkinson's disease (PD) is a neurodegenerative disorder with progressive motor and non-motor symptoms. Conventional treatments mainly manage symptoms, not causes, highlighting the need for new therapies. Natural phytochemicals, particularly phenolic compounds, show potential due to neuroprotective effects. Antiaris africana is used in traditional African medicine for illnesses, including neurodegenerative disorders. However, its neuroprotective mechanism remains unclear. This study integrated network pharmacology, molecular docking, and molecular dynamics simulations to examine the neuroprotective potential of A. africana compounds against PD. Using GeneCards, SwissTargetPrediction, and STITCH databases, 256 Parkinson-related targets intersecting with 11 phytocompounds were identified. Hub genes TP53, EGFR, AKT1, CASP3, ESR1, SRC were enriched in pathways regulating neuroinflammation, apoptosis, and kinase signaling. Molecular docking showed strong interactions between rutin, isoquercitrin, and ellagic acid with multiple targets, with isoquercitrin-AKT1 showing highest binding affinity. Molecular dynamics simulations showed these ligands stabilized proteins, reduced flexibility, compacted conformations, and minimized solvent exposure. Rutin formed persistent hydrogen bonds with EGFR, ESR1, SRC, and TP53, while MMGBSA analysis showed favorable binding energetics, particularly for ESR-rutin. Principal component analysis and dynamic cross-correlation matrices revealed ligand-induced conformational changes that may promote protective protein states. From this we, hypothesize that phenolic compounds in A. africana may confer neuroprotection in PD by stabilizing signaling proteins to modulate apoptosis, neuroinflammation, and proteostasis. While promising, these findings from in-silico analyses require experimental validation to confirm translational relevance. Nevertheless, the study provides a mechanistic basis for elucidating the neuroprotective role of A. africana and supporting its exploration as a source of disease-modifying agent for PD.