Therapeutic Potential of products derived from Pluchea lanceolata for Alzheimer’s Disease Treatment

AD is a neurodegenerative disorder and is associated with the presence of amyloid-β plaques and neurofibrillary tangles leading to net loss of neurons, which demonstrates an urgent unmet need to develop new human health therapies based on the fundamental mechanisms of oxidative stress and neuroinflammation. This work is a computational assessment of the potential use of neolupenol, a triterpenoid produced in Pluchea lanceolata, as a pharmacologically active compound that exerted its beneficial effect through the modulation of the Keap1-Nrf2 axis, one of the central regulators of the antioxidant response. Using an integrated approach that combined network pharmacology, molecular docking, and molecular dynamics (MD) simulations, we identified neolupenol as a high-affinity Keap1-binding molecule capable of activating the Nrf2-mediated neuroprotective pathway. Virtual screening of 25 phytochemicals from Pluchea lanceolata (retrieved from the PubChem database) with customized filters revealed neolupenol as the top candidate, showing strong binding affinity (− 8.22 kcal/mol; Ki = 1.45 µM) toward the Keap1 Kelch domain (PDB ID: 2FLU). The docked complex demonstrated hydrogen bonds with VAL463 (2.17 Å), THR560, and ILE559, along with hydrophobic interactions involving CYS513, ALA366, and VAL514, which collectively stabilized the ligand at the Neh2-binding interface. Network pharmacology yielded 30 of such common targets of AD-neolupenol (e.g., GSK3B, CASP3, TNF, and BACE1), enriched in pathways such as amyloid processing, tau phosphorylation, oxidative stress response, and lipid metabolism (FDR-adjusted p < 0.0001). Complex stability was verified by MD simulations (100 ns): RMSD of the backbone 2.34–3.84 = 2.34 Å, unchanged radius of gyration (17.8–18.0 Å), and stable inter-hydrogen bonding. Residues VAL561, PHE577, and SER602 were found to have an interaction occupancy of > 70%, providing a basis of dynamic stability. The triterpenoid cavity appeared in neolupenol contributing to pleasant PK, the ability to herald the blood–brain barrier, and suboptimal toxicity. These results position neolupenol as a potent, multi-target neuroprotective agent that disrupts Keap1–Nrf2 interaction, promoting Nrf2 nuclear translocation and antioxidant gene activation. Future work warrants in vivo validation of its efficacy in mitigating AD pathology and clinical translation.

Graphical Abstract