Do_2025_RSC.Adv_15_12866

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and memory loss, with amyloid-beta (Abeta) plaques and acetylcholine deficits being central pathological features. Inhibition of dual targets including acetylcholinesterase (AChE) and beta-site amyloid precursor protein cleaving enzyme 1 (BACE-1) represents a promising strategy to address cholinergic deficits and amyloid pathology. In this study, we used computational approaches to evaluate 8000 tripeptides as potential dual inhibitors of AChE and BACE-1. Machine learning models revealed the four top-lead tripeptides including WHM, HMW, WMH, and HWM. Molecular docking simulations indicated that WHM possessed the most favorable interactions through hydrogen bonds, Pi-Pi stacking, and salt bridges with key catalytic residues in both enzymes. Molecular dynamics simulations confirmed the stability of the protein-ligand complexes, with WHM exhibiting the most consistent conformations and significant disruption of catalytic residue geometries. Free energy perturbation analysis further supported WHM's superior stability across both targets. ADMET predictions suggested moderate oral absorption and limited brain penetration, consistent with the typical behavior of peptide-based compounds. Overall, WHM demonstrated the strongest potential as a dual inhibitor of AChE and BACE-1, offering a promising lead for future therapeutic development in AD.