物理化学学报 >> 2009, Vol. 25 >> Issue (07): 1379-1384.doi: 10.3866/PKU.WHXB20090720

研究论文 上一篇    下一篇

乙酰胆碱酯酶抑制剂Corydaline的分子对接与开环衍生物的虚拟筛选

蒋玉仁, 许慧, 陈芳军, 马贯军   

  1. 中南大学化学化工学院, 长沙 410083
  • 收稿日期:2009-01-21 修回日期:2009-03-19 发布日期:2009-06-26
  • 通讯作者: 蒋玉仁 E-mail:jiangyr@mail.csu.edu.cn; xuhui0820@163.com

Molecular Docking of the Acetylcholinesterase Inhibitor Corydaline and Virtual Screening of Open Ring Derivatives

JIANG Yu-Ren, XU Hui, CHEN Fang-Jun, MA Guan-Jun   

  1. College of Chemistry and Chemical Engineering, Central South University, Changsha 410083, P. R. China
  • Received:2009-01-21 Revised:2009-03-19 Published:2009-06-26
  • Contact: JIANG Yu-Ren E-mail:jiangyr@mail.csu.edu.cn; xuhui0820@163.com

摘要:

用分子对接软件GOLD, 研究了延胡索类生物碱corydaline与乙酰胆碱酯酶的结合模型, 并虚拟筛选了一系列具有不同碳链长度和取代基的开环衍生物以指导潜在高活性化合物的合成. 分子对接结果表明, corydaline与开口构象的酶结合可能性最大. 结合模型显示, corydaline的A环与外周阴离子位点Tyr334产生π-π堆积; 质子化氮原子与疏水位点Phe330产生阳离子-π作用; 而D环上的甲氧基则深入到活性口袋底部占据催化位点. 开环衍生物虚拟筛选发现, 大部分化合物的得分均高于母体, 得分排名前15位的化合物主要为被苄氧基等大基团取代且连接碳链长为2-7的衍生物. 基于预测结果, 合成了化合物7, 其抑制活性为现有药物加兰他敏的3倍.

关键词: Corydaline, 乙酰胆碱酯酶, 分子对接, 开环衍生物, 虚拟筛选

Abstract:

We used molecular docking software GOLD to investigate the binding mode of corydaline, a type of cordalis alkaloid, with acetylcholinesterase and to screen a series of open ring derivatives with different carbon linkages and different substituent groups. The best result was obtained when corydaline was bound to the enzyme catalytic site in an open conformation. The conformation model indicates that phenyl ring A interacts with the phenyl group of Tyr334 via a classic parallel π-π accumulation and that the positively charged nitrogen atom interacts with the phenyl group of Phe330 in the hydrophobic site by the cation-π effect. Both dimethoxy radicals of phenyl D that penetrate to the bottom of the active pocket interact at the catalytic position. Virtual screening showed that the scores of most derivatives were higher than that of corydaline and that the 15 open ring substances with the highest scores were mainly derived from those substituted by phenoxy groups and those with 2 to 7 carbon linkages. Based on these virtual screening results, compound 7 was synthesized and a pharmacological study showed that its inhibition activity was three times as high as galanthamine.

Key words: Corydaline, Acetylcholinesterase, Molecular docking, Open ring derivative, Virtual screening

MSC2000: 

  • O641