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石杉碱甲是我国首先从石杉属植物Haperzia serrata(Thunb.)Trev.中分离得到的一种新的生物碱,具有明显的抗胆碱酯酶作用,对老年痴呆病人可明显改善其记忆功能。从基于酶的三维结构出发对石杉碱甲及其类似物作用于乙酰胆碱酯酶(AChE)的作用机理进行了理论计算研究。首先以同源的电鳐乙酰胆碱酯酶的三维晶体结构为模板,构建人乙酰胆碱酯酶(H.AChE)的三维结构和活性中心的组成,再用分子模拟方法和分子力学方法得到石杉碱甲类似物-AChE复合物的结构,并计算石杉碱甲和AChE结合时的相互作用能,发现其与活性之间有相关性。用半经验量子化学计算方法AM1计算了石杉碱甲类似物活性构象的电子结构,用偏最小二乘(PLS)方法对上述相互作用能、HOMO和LUMO轨道能级对活性进行回归,得到了活性与上述参数间的定量构效关系,发现石杉碱甲类似物与AChE可能形成电荷转移复合物,并且两者之间的前线轨道参数与石杉碱甲类化合物与AChE的相互作用,进而影响石杉碱甲的活性。
Huperzine A is a new alkaloid isolated from the genus Haperzia serrata (Thunb.) Trev. It has obvious anticholinesterase activity and can significantly improve its memory in patients with Alzheimer’s disease Features. The mechanism of action of huperzine A and its analogues on acetylcholinesterase (AChE) was theoretically studied based on the three-dimensional structure of enzyme. Firstly, the three-dimensional crystal structure of human acetylcholinesterase (H.AChE) was constructed by using the three-dimensional crystal structure of homologous acetylcholinesterase as template, and the composition of the three-dimensional structure and active center of human acetylcholinesterase (H.AChE) was constructed. Then the molecular modeling method and molecular mechanics method were used to obtain huperzine A Analog-AChE complex structure, and calculate the interaction energy of Huperzine A and AChE binding, found that there is a correlation between activity. The electronic structure of the active conformation of huperzine A analogues was calculated by semi-empirical quantum chemical calculation method AM1. The interaction energy, HOMO and LUMO orbital energy levels were calculated by partial least squares (PLS) Activity and the quantitative structure-activity relationship between the above parameters and found that huperzine A analogs and AChE may form a charge transfer complex, and the front orbital parameters between the two Huperzine A and AChE interactions, and thus Huperzine A affect the activity.