Nour Hassan, Abchir Oussama, Mounadi Nouh, Samadi Abdelouahid, Salah Belaidi, Chtita Samir
Laboratory of Analytical and Molecular Chemistry, Faculty of Sciences Ben M'Sik, Hassan II University of Casablanca, Casablanca, 7955, Morocco.
Department of Chemistry, College of Science, UAEU, P.O. Box No. 15551, Al Ain, United Arab Emirates.
Heliyon. 2025 Feb 5;11(4):e42479. doi: 10.1016/j.heliyon.2025.e42479. eCollection 2025 Feb 28.
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.
胆碱酯酶（丁酰胆碱酯酶和乙酰胆碱酯酶）是阿尔茨海默病对症治疗中重要的生物学靶点。事实上，抑制胆碱酯酶已被证明可改善阿尔茨海默病患者的神经传递机制。在本研究中，我们试图从天然产物中筛选出新的胆碱酯酶抑制剂。为此，利用分子对接、药代动力学和毒理学分析对28种药用植物的次生代谢产物（299种植物成分）进行了虚拟筛选。10种植物成分（L82、L86、L92、L121、L148、L187、L211、L221、L228）与丁酰胆碱酯酶表现出高结合亲和力，5种植物成分，即L119、L147、L149、L192和L193，与乙酰胆碱酯酶表现出强结合能力。随后，对这些植物成分的药物代谢动力学性质进行了评估。结果显示，L221预计具有高生物利用度，能被人体肠道轻易吸收且无明显毒性问题，适合口服给药。至关重要的是，它能够穿透血脑屏障（BBB），从而有效到达中枢神经系统。分子动力学模拟和MM-PBSA分析表明，筛选出的最佳植物成分与丁酰胆碱酯酶结合位点形成热力学上有利且稳定的复合物。所进行的研究突出了有前景的结果，可为有效胆碱酯酶抑制剂的合理开发提供方向。
