Exploring flavonoids as multi-target therapeutic agents in Alzheimer’s disease: Insights from Network Pharmacology, Molecular Docking, and Dynamics

Alzheimer’s disease (AD) is a neurodegenerative illness that causes tau aggregation and amyloid-beta plaque accumulation in the brain, which gradually impairs memory and cognition. Despite extensive research, current therapeutic options remain limited and often carry significant side effects. This study explores flavonoids, bioactive plant-derived compounds, as potential treatment candidates with multi-target activity against AD. A total of 55 flavonoids, selected based on neuroprotective relevance and retrieved from the PubChem database, were screened for their multi-target potential against AD. A comprehensive approach integrating systems pharmacology (SwissTarget, GeneCards, STRING), network visualization and hub analysis (Cytoscape), enrichment analysis (DAVID, SRplot), correlation validation (GEPIA), drug-likeness and ADMET profiling (SwissADME, pkCSM, ProTox-II), molecular docking (Maestro–Schrödinger), and molecular dynamics simulations (Desmond) was employed to uncover the molecular basis of flavonoids’ neuroprotective effects. Through systems pharmacology, essential AD-related targets were identified, and a protein–protein interaction network was developed, highlighting 32 common targets. Enrichment analysis revealed critical pathways in AD pathogenesis, including MAPK signaling, apoptotic processes, and amyloid precursor protein processing. Computational docking revealed high interaction strengths of flavonoids, specifically morin, luteolin, and genistein, against key AD-associated targets, including acetylcholinesterase, β-site APP cleaving enzyme 1, glycogen synthase kinase-3 beta, and dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A). Morin demonstrated the strongest binding affinity with a Glide XP docking score of –9.277 kcal/mol against DYRK1A, outperforming luteolin (–9.256 kcal/mol) and genistein (–9.133 kcal/mol). Molecular simulations further confirmed the stability of the Morin–DYRK1A complex (RMSD <3 Å over 150 ns). These results indicate that flavonoids may exhibit promise as treatment candidates for AD.