Unveiling AKT1 as a key target of β-asarone in Alzheimer’s disease through network pharmacology and molecular dynamics simulations

Abstract

Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by cognitive decline and complex, multi-factorial pathology. Current single-target drugs provide only limited benefits, and there is a need for more effective therapeutic strategies. β-asarone, a major volatile component of Acorus tatarinowii used in traditional Chinese medicine (TCM), has demonstrated neuroprotective effects, including anti-apoptotic, anti-inflammatory, and anti-amyloid β (Aβ) toxicity properties. However, the molecular targets and signaling mechanisms of β-asarone in AD remain underexplored. Objective: This study aims to explore the molecular targets and signaling mechanisms of β-asarone in AD by integrating network pharmacology, molecular docking, and molecular dynamics simulations. Methods: Network pharmacology was used to identify overlapping targets between β-asarone and AD. Protein-protein interaction networks were constructed using STRING, and key targets were analyzed for enrichment in the PI3K-AKT/MAPK pathways. Molecular docking was conducted to assess the binding affinity of β-asarone with multiple targets along the PI3K-AKT axis. Additionally, molecular dynamics (MD) simulations of the β-asarone-AKT1 complex were performed for 100 ns to assess the stability of the interaction. Results: Seventy-four overlapping targets of β-asarone and AD were identified, with key hub genes enriched in the PI3K-AKT/MAPK pathways. Molecular docking revealed that β-asarone binds to critical nodes along the PI3K-AKT axis with binding free energies (ΔG) of approximately −6.2 kcal/mol and to HRAS/IGF1 with ΔG ≈ −5.2/−4.1 kcal/mol. MD simulations showed stable trajectories for the β-asarone-AKT1 complex (RMSD ~3.5–4.0 Å) with persistent hydrogen bonds, indicating a durable interaction in the ATP-binding pocket. Conclusion: β-asarone interacts with multiple interconnected signaling nodes, particularly the PI3K-AKT pathway, to modulate apoptosis, neuroinflammation, and cellular energetics. These findings support the potential of β-asarone as a TCM-derived candidate for the development of therapeutic strategies for AD.