Nour_2025_Heliyon_11_e42479

Cholinesterase enzymes (BuChE and AChE) are privileged biological targets for the symptomatic treatment of Alzheimer's disease. Indeed, inhibition of cholinesterase enzymes has been proven to improve the neurotransmission mechanisms in Alzheimer's disease patients. In this investigation, we attempt to highlight new cholinesterase inhibitors from natural products. For this purpose, secondary metabolites (299 phytoconstituents) of twenty-eight Medicinal plants were virtually screened using molecular docking, pharmacokinetic and toxicological analysis. Ten phytoconstituents (L82, L86, L92, L121, L148, L187, L211, L221, L228) exhibited their high binding affinity with BuChE, and five phytoconstituents, namely L119, L147, L149, L192 and L193, exhibited their strong binding ability with AChE. Subsequently, these phytoconstituents were evaluated for their ADMET properties. As result, L221 is predicted to be highly bioavailable and readily absorbed by the human intestinal tract without significant toxicity concerns, making it suitable for oral administration. Crucially, it can penetrate the blood-brain barrier (BBB), allowing it to effectively reach the central nervous system. Molecular dynamics simulations and MM-PBSA analysis revealed that the best-screened phytoconstituent form thermodynamically favorable and stable complex with the BuChE binding site. The conducted investigations highlighted promising outcomes that can orient towards the rational development of effective Cholinesterase inhibitors.