1. 毕业设计（论文）的内容和要求

(1) 通过查阅文献，了解该课题的国内外研究现状；(2) 学习和掌握有关计算软件的使用；(3) 乙酰胆碱酯酶AChE与抑制剂小分子（苄基哌啶类抑制剂）为研究体系，利用模拟软件对体系进行模拟计算，分析体系在溶剂中的构象变化及AChE与抑制剂的作用机制；(4) 分析计算结果，撰写毕业论文。

预定完成任务及时间： 2016年6月7日。

2. 参考文献

[1] Zhu, X. L.; Yu, N. X.; Hao, G. F.; Yang, W. C.; Yang, G. F., Structural basis of femtomolar inhibitors for acetylcholinesterase subtype selectivity: insights from computational simulations. Journal of molecular graphics modelling 2013, 41, 55-60. [2] Puiatti, M.; Borioni, J. L.; Vallejo, M. G.; Cabrera, J. L.; Agnese, A. M.; Ortega, M. G.; Pierini, A. B., Study of the interaction of Huperzia saururus Lycopodium alkaloids with the acetylcholinesterase enzyme. Journal of molecular graphics modelling 2013, 44, 136-44. [3] 邹磊, 全明海, 程永强, 李里特. 乙酰胆碱酯酶抑制剂的研究进展. 食品科学, 2005, 26: 105-108. [4] 周金培, 黄文龙, 张惠斌. 乙酰胆碱酯酶抑制剂的研究进展. 药学进展, 1998, 22: 65-68. [5] Fan, F.; You, Z.; Li, Z.; Cheng, J.; Tang, Y.; Tang, Z., A butterfly effect: highly insecticidal resistance caused by only a conservative residue mutated of drosophila melanogaster acetylcholinesterase. Journal of molecular modeling 2009, 15, 1229-36. [6] Fang, L.; Pan, Y.; Muzyka, J. L.; Zhan, C. G., Active site gating and substrate specificity of butyrylcholinesterase and acetylcholinesterase: insights from molecular dynamics simulations. The journal of physical chemistry. B 2011, 115, 8797-805. [7] Andrea Cavalli, G. B., Caterina Raco, Marco De Vivo, and Maurizio Recanatini*, A Computational Study of the Binding of Propidium to the Peripheral Anionic Site of Human Acetylcholinesterase. J. Med. Chem. 2004, 47, 3991-3999. [8] 朱丽霞. 治疗阿尔茨海默氏病的胆碱酯酶抑制剂研究进展. 四川生理科学杂志, 2002, 24: 60-63. [9] 张赟彬, 宋庆, 胡刘岩. 天然产物中乙酰胆碱酯酶抑制剂的研究现状. 上海应用技术学院学报(自然科学版), 2011, 11 (1). [10] Jennifer M. Bui, K. T., and J. Andrew McCammon Acetylcholinesterase: Enhanced Fluctuations and Alternative Routes to the Active Site in the Complex with Fasciculin-2. J. AM. CHEM. SOC. 2004, 126, 7198 - 7205. [11] Araujo, J. Q.; Lima, J. A.; Pinto Ada, C.; de Alencastro, R. B.; Albuquerque, M.G., Docking of the alkaloid geissospermine into acetylcholinesterase: a natural scaffold targeting the treatment of Alzheimer's disease. Journal of molecular modeling 2011, 17, 1401-12. [12] Alpan, A. S.; Parlar, S.; Carlino, L.; Tarikogullari, A. H.; Alptuzun, V.; Gunes, H. S., Synthesis, biological activity and molecular modeling studies on 1H-benzimidazole derivatives as acetylcholinesterase inhibitors. Bioorg Med Chem 2013, 21, 4928-37. [13] Spilovska, K.; Korabecny, J.; Horova, A.; Musilek, K.; Nepovimova, E.; Drtinova, L.; Gazova, Z.; Siposova, K.; Dolezal, R.; Jun, D.; Kuca, K., Design, synthesis and in vitro testing of 7-methoxytacrine-amantadine analogues: a novel cholinesterase inhibitors for the treatment of Alzheimer#8217;s disease. Medicinal Chemistry Research 2015, 24, 2645-2655. [14] Wiesner, J.; Kriz, Z.; Kuca, K.; Jun, D.; Koca, J., Influence of the acetylcholinesterase active site protonation on omega loop and active site dynamics. Journal of biomolecular structure dynamics 2010, 28, 393-403.

3. 毕业设计（论文）进程安排

2016-02-25~2016-03-25 系统地检索和阅读相关中外文文献，了解该课题的国内外研究现状。

对ache的结构和性质，计算机模拟软件gaussian 09、autodock4.0、amber 10，前人的研究等有所了解，完成开题报告。

2016-03-25~2016-05-10 进一步学习和掌握有关计算软件的使用，用gaussian 09优化苄基哌啶类抑制剂的几何结构，并利用autodock4.0将其最优结构和ache进行对接。