Neuroprotective curcuminoids from Curcuma longa as multi-target-directed ligand therapeutics for Alzheimer’s disease: an integrated in silico and in vivo approach

Alzheimer’s disease (AD) is a chronic, multifactorial neurodegenerative disorder characterized by progressive cognitive decline and memory loss. Pathological hallmarks include extracellular amyloid-β (Aβ) deposition and intracellular neurofibrillary tangles (NFTs) in brain cells, which drive neuronal degeneration and dementia. Current drugs provide only symptomatic relief, with limited efficacy and adverse side effects, underscoring the need for novel therapeutics. In this study, phytochemicals from Curcuma longa were screened for drug-likeness using ADME and pharmacokinetic analyses, identifying curcuminoids—curcumin, demethoxycurcumin, and bisdemethoxycurcumin—as bioavailable candidates. Molecular docking (MD) revealed strong binding affinities for AD therapeutic targets, including acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), glycogen synthase kinase-3β (GSK-3β), β-secretase, and γ-secretase (− 11.07 to − 22.70 kcal/mol), suggesting multi-target inhibitory potential. MD simulations (100 ns) demonstrated structural stability, with demethoxycurcumin showing the lowest RMSD values (~ 0.13–0.18 nm for AChE). MM-GBSA free energy calculations confirmed favorable binding (ΔG_binding − 23.35 kcal/mol for β-secretase–demethoxycurcumin and − 21.68 kcal/mol for BuChE–demethoxycurcumin). In vivo validation using an Aβ 42 -expressing Drosophila model showed dose-dependent reductions in cholinesterase activity (60–75% at 5 mg/mL, p < 0.05), suppression of AD-associated proteins (Aβ 42 : ~50–60%; BACE1: ~30–40%; GSK-3β: ~50–60%; KEAP1: ~30–40%), lifespan extension (27.98 → 38.66 days, p < 0.001), and improved motor activity (climbing index ~ 0.70 → ~0.90–1.00, p < 0.001). Collectively, these findings highlight curcuminoids as a promising multi-target-directed ligand for AD therapy, warranting further validation in higher-order animal models.