Density functional theory analysis on the molecular structures and properties of drugs for Alzheimer's disease
YAN Xixi 1, 2, HUANG Luoyi1, WANG Chaojie1, XIANG Zheng1
1.School of Pharmaceutical Sciences,Wenzhou Medical University, Wenzhou 325035, China; 2.Department of Pharmacy, the Seventh People’s Hospital of Wenzhou, Wenzhou 325000, China
YAN Xixi,HUANG Luoyi,WANG Chaojie, et al. Density functional theory analysis on the molecular structures and properties of drugs for Alzheimer's disease[J]. JOURNAL OF WEZHOU MEDICAL UNIVERSITY, 2020, 50(12): 955-960.
Abstract：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.
