Lead Discovery from Hippophae Rhamnoides: A Systems Biology Approach to Target Differentially Expressed Genes in Alzheimer's Disease

Alzheimer's disease (AD), a neurodegenerative disorder characterized by cognitive decline and neuronal dysfunction, continues to pose significant therapeutic challenges. Current treatments provide limited symptomatic relief, underscoring the urgent need for novel and effective interventions. Leveraging the therapeutic potential of natural bioactive compounds, this study explores Hippophae rhamnoides (HR) as a source of multi-targeted agents against AD. A systems biology approach was employed, incorporating virtual screening, hub-bottleneck gene mapping, pathway enrichment analysis, molecular docking, and dynamics simulations. Promising candidates, including Harmine, Dihydroresveratrol, Emodin, and Quercetin, were identified based on favorable ADME properties. Hub-bottleneck analysis revealed key proteins such as ESR1, MAPK1, PIK3CA, and AKT1, with KEGG pathway analysis emphasizing the roles of the Estrogen Signaling and PI3K-Akt Signaling pathways in AD pathogenesis. Molecular docking and dynamics simulations confirmed stable interactions between these bioactives and target proteins, highlighting specific residues as potential sites for optimization. These findings advance the understanding of HRderived compounds as therapeutic leads, paving the way for multitargeted drug development for Alzheimer's disease.