Computer-based Identification of New Acetylcholinesterase Inhibitory Secondary Metabolites from Medicinal Plants Used for Treating Alzheimer’s Disease

Alzheimer’s disease (AD) is the major form of dementia globally. It mainly affects the elderly population and progression to severe stages of AD is fatal. Acetylcholinesterase (AChE) is a key anti-Alzheimer’s drug target and its effective inhibition reduces the symptoms and the progression of AD. With the aim of identifying potential AChE inhibitors, a molecular docking protocol targeting the active site of human AChE was pre-validated using a drug-like molecular library containing known AChE inhibitors and known non-inhibitors. A library of 1608 phytochemicals from 29 different medicinal plants and clinically approved AChE inhibitors donepezil, rivastigmine and galantamine were then screened using the same protocol. Thirty-two compounds including 24 previously reported AChE inhibitors by in vitro studies and 8 previously unreported potential AChE inhibitors were identified by virtual screening. Eight new AChE inhibitors thus identified were predicted to be non-hepatotoxic drug-like compounds with high oral absorption. Molecular Dynamics (MD) simulations indicated that five out of eight secondary metabolites (diffusarotenoid, asacoumarin A, lysergic acid alpha-hydroxyethyl amide, ferocolicin and dehydropipernonaline) form stable complexes with AChE. In comparison to positive controls, all five secondary metabolites exhibited more negative binding free energies as calculated by Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) calculations. All five secondary metabolites formed interactions with the peripheral anionic site (PAS) of AChE, suggesting that they may also inhibit neurotoxic Aβ–AChE complexes formation that mediates through PAS. Asacoumarin A and dehydropipernonaline targeted both PAS and the catalytic site. However, further experimental studies are required for validating these results.