乙酰胆碱酯酶抑制剂多奈哌齐衍生物的理性设计

Rational design of acetylcholinesterase inhibitor based on donepezil

阿尔茨海默症是老年人群中常见的慢性神经退行性疾病,严重损害老年人健康与生活质量.目前临床常使用乙酰胆碱酯酶抑制剂多奈哌齐等作为治疗药物.本文通过分子模拟方法研究了多奈哌齐和乙酰胆碱酯酶的作用模式;基于研究结果,对多奈哌齐衍生物进行理性设计,获得了化合物1.分子对接及药代动力学性质预测结果显示,化合物1具有和多奈哌齐相似的作用模式和成药性质.同时,分子静电势表面分布结果显示,甲基的引入可增强化合物1与关键氨基酸残基F295之间的氢键相互作用,可能具有较多奈哌齐更理想的活性.此外,化合物1能制备得到稳定的光学纯异构体;有利于减少临床上药物的使用量,降低副作用发生几率,具有进一步研究的价值.

Alzheimer’s disease is a common chronic neurodegenerative disease in the elderly, which seriously damages their health and quality of life. At present, acetylcholinesterase inhibitor donepezil is often used clinically as a therapeutic drug. This paper intends to study the action mode of donepezil and AChE by molecular simulation. Based on the results, compound 1 was obtained by rational design from donepezil. The results of molecular docking and ADMET prediction show that compound 1 has a similar mode of action and as considerable druggability as donepezil. At the same time, the molecular electrostatic potential surfaces of donepezil and compound 1 show that compound 1 can enhance the hydrogen bond interaction with the key residue F295 due to the introduction of the methyl group to some extent, and may have more ideal pharmacological activity than donepezil. In addition, compound 1 can prepare stable optically pure isomers;it is beneficial to reduce the clinical dosage of drugs and the probability of side effects, which is of value for further research.