Deciphering the acetylcholinesterase inhibitory potential of artemisinin and artesunate: An in-silico approach

Acetylcholinesterase (AChE) is a key therapeutic target in Alzheimer's disease, and the identification of novel inhibitors remains an important research objective. In this study, the AChE inhibitory potential of artemisinin and artesunate was investigated using molecular docking, molecular dynamics (MD) simulations, density functional theory (DFT) calculations, and in silico ADME analysis. Molecular docking against human AChE (PDB ID: 4EY7) showed binding affinities of −10.2 and −10.0 kcal/mol for artemisinin and artesunate, respectively, compared with −8.1 kcal/mol for rivastigmine and −11.8 kcal/mol for donepezil. Both compounds established interactions with key active-site residues involved in AChE inhibition. MD simulations were performed for apo AChE and the AChE–donepezil complex (as controls) and for the artesunate and artemisinin complexes. The Cα-RMSD was 1.2–2.4 Å for apo AChE and 1.0–2.3 Å for the donepezil complex. The artesunate complex was closer to these references (1.5–3.6 Å), whereas the artemisinin complex showed greater backbone movement (3.6–4.8 Å). HOMO–LUMO gaps were 7.05 and 6.94 eV for artemisinin and 6.67 and 6.76 eV for artesunate in vacuum and water, respectively. Both compounds showed high gastrointestinal absorption, no Lipinski violations, and bioavailability scores of 0.55–0.56, and artemisinin was predicted to cross the blood–brain barrier. Taken together, artesunate showed the protein stability closest to donepezil, whereas artemisinin was predicted to cross the blood–brain barrier, suggesting that each compound has complementary strengths and that both warrant further optimisation and experimental evaluation as AChE-targeting scaffolds.