Computational Discovery of Multi-Target CNS-Active Phytochemicals for Alzheimer's Disease: (+)-Boldine and Epicatechin as Candidate Dual-Action Compounds

Alzheimer's disease (AD) arises from the convergence of amyloidogenesis, tau dysregulation, cholinergic failure, oxidative stress, and excitotoxicity, requiring therapeutic strategies capable of engaging multiple pathogenic pathways simultaneously. Here, we performed a multi-stage in silico drug-discovery pipeline to identify natural product–derived compounds with CNS drug-likeness, safety, and multi-target binding potential. Thirteen phytochemicals were screened against five validated AD targets—BACE1, AChE, BChE, GSK-3, and the NMDA receptor—integrating molecular docking, pharmacokinetic profiling (SwissADME), and toxicity prediction (ProTox-III). This funnel narrowed the panel to two compounds, the alkaloid (+)-boldine and the flavonoid epicatechin, on the basis of favorable toxicity profiles and strong docking affinities (maximum ΔG = −9.9 kcal/mol). Their pharmacokinetic profiles are not uniformly favorable, however: (+)-boldine was the only one of the two predicted as blood–brain barrier (BBB)-permeant by the SwissADME BOILED-Egg model, and both compounds were flagged as putative P-glycoprotein (P-gp) substrates; epicatechin's retention as a candidate rests on independent literature evidence of measurable brain penetration rather than on the in silico permeability prediction. To test whether the docking-predicted poses correspond to stable, energetically favorable complexes, we performed 100-ns all-atom molecular dynamics (MD) simulations of the (+)-boldine– and epicatechin–acetylcholinesterase (AChE, PDB 4EY7 ) complexes, benchmarked against the clinically used AChE inhibitor donepezil as a reference ligand. Both phytochemicals formed stable complexes over the full trajectory, with protein/ligand RMSD, radius of gyration, and key-contact occupancy comparable to or better than the donepezil reference. MM-GBSA binding free energies were comparable across all three ligands (donepezil −24.9 ± 4.2, epicatechin −24.0 ± 3.9, (+)-boldine −22.7 ± 3.7 kcal/mol), while MM-PBSA estimates on the same trajectories were internally inconsistent and are reported only as a methodological limitation. Epicatechin sustained substantially more persistent hydrogen bonding than donepezil or (+)-boldine (mean 3.2 vs. 0.5 and 0.8 bonds, respectively), indicating a distinct, hydrogen-bond-driven binding mode. Because dynamic validation was performed only for the AChE complexes and the two free-energy methods disagreed, we present (+)-boldine and epicatechin as promising, mechanistically distinct AChE-directed candidates for further validation rather than as confirmed multi-target leads, and outline the additional target-by-target and experimental validation required to support that stronger claim.