五种治疗阿尔茨海默病药物分子结构与性质的密度泛函计算分析

目的：在模拟大脑油性环境下对五种抗阿尔茨海默病药物进行整体和局部性质计算比较分析。方法：采用密度泛函B3LYP/TZVP计算方法，对五种抗阿尔茨海默病药物的几何结构、电子结构、紫外光谱和概念密度泛函分析，利用环己烷模拟大脑油性环境。结果：共轭效应使得极性键键长缩短；静电势差异决定了分子间作用位点的不同，在酶反应中，与蛋白质构象的改变密切相关；溶剂效应对紫外光谱产生影响，其中溶剂的极性越大红移越大。由福井函数结合相对亲电指数与相对亲核指数，表明多奈哌齐和卡巴拉汀亲电、亲核能力都很强，加兰他敏亲核能力强，美金刚和石杉碱甲亲电、亲核能力均比较弱。结论：五种药物分子的结构差异、电性差异影响药物的理化性质并决定了药物不同的作用机制。四种抗胆碱酯酶抑制剂活性略有差异但明显高于N-甲基-D-天冬氨酸受体拮抗剂，其中多奈哌齐药理作用最强。

Density functional theory analysis on the molecular structures and properties of drugs for Alzheimer's disease

Objective: To compare the global and local properties of the five anti-Alzheimer’s drugs through computation and analysis in a simulated brain oil environment by cyclohexane. Methods: Based on the density function theory, the B3LYP methods with TZVP basis set was used to investigate the molecular structures, UV-Vis spectra, frontier molecular orbital, molecular surface electrostatic potential and conceptual density function of the five anti-Alzheimer disease drugs by simulating an oil brain environment by cyclohexane. Results: Conjugative effect shortened the polar bond length, andt he difference of electrostatic potential determined the difference of intermolecular action sites, which was closely related to the change of protein conformation in enzyme reaction.Solvent effect had an impact of UV-V is spectrum, in which the more the polarity of solvent, the more red-shift phenomenon of UV spectrum of compound was produced. The Fukui function in combination with the relativeelectrophilic index and the relative nucleophilic index showed thatdonepezil and rivastigmine were both highly electrophilic and nucleophilic, while galanthamine was highly nucleophilic only; in contrast, memantine and huperzine had weak electrophilic and nucleophilic ability. Conclusion: The molecular difference in geometric and electric structures of the five drugs affects the physicochemical properties of the drugs and determines the different mechanisms of action. The activities of four cholinesterase inhibitors (ChEI) were similar but significantly higher than those of N-methyl-D-aspartic acid receptor (NMDAR) antagonists, on which donepezil has the strongest pharmacological effect.