物理化学学报 >> 2005, Vol. 21 >> Issue (05): 474-478.doi: 10.3866/PKU.WHXB20050503

研究论文 上一篇    下一篇

α-芋螺毒素构效关系与分子设计

胡亚兰; 黄锋; 蒋辉; 范崇旭; 陈常英; 陈冀胜   

  1. 北京药物化学研究所, 北京 102205
  • 收稿日期:2004-09-20 修回日期:2004-12-01 发布日期:2005-05-15
  • 通讯作者: 黄锋 E-mail:huangfeng_71@yahoo.com.cn

Structure-Activity Relationship and Molecular Design ofα-conotoxins

HU Ya-Lan; HUANG Feng; JIANG Hui; FAN Chong-Xu; CHEN Chang-Ying; CHEN Ji-Sheng   

  1. Beijing Institute of Pharmaceutical Chemistry, Beijing    102205
  • Received:2004-09-20 Revised:2004-12-01 Published:2005-05-15
  • Contact: HUANG Feng E-mail:huangfeng_71@yahoo.com.cn

摘要: α-芋螺毒素(α-conotoxins)是从芋螺毒液中提取到的一类活性多肽. 与其它家族的芋螺毒素相比, 它们含二硫键少, 结构相对简单, 由于作用于神经肌肉接头的N-乙酰胆碱受体(nAChRs)的不同亚型, 拮抗乙酰胆碱, 可作为鉴定nAChRs亚型及其亚基的有效工具, 已成为芋螺毒素结构改造的最佳先导化合物. 利用HyperChem软件包的量子化学半经验方法AM1对8个具有代表性的α-芋螺毒素进行了量子化学计算, 研究了它们的电子结构及构效关系. 结果表明, 空间结构的相似性使它们作用于同一受体, 局部结构差异而导致的电子结构的较大差别是它们能作用于不同受体亚型的重要原因. 在此基础上, 以α-芋螺毒素GI为模型设计了7个类似物并进行了量子化学计算, 比较了类似物与GI在空间结构及电子结构方面的特征.

关键词: α-芋螺毒素, 乙酰胆碱受体, 电子结构, 构效关系, 分子设计

Abstract: α-conotoxins, extracted from conus venoms, are a family of active peptides. The most characteristic and predominant features of these small peptides are fewer disulfide bonds, simpler structure, and higher toxicity compared with other families of conotoxins that they have antagonists of nicotinic acetylcholine and target to subtypes of nicotinic acetylcholine receptor at neuromuscular junction, α-conotoxins make themselves effective tools for identifying the subtypes of nicotinic acetylcholine receptors and the best lead compounds for reconstructing structures of conotoxins. Electronic structures of eight typicalα-conotoxins were calculated by quantum chemical semi-empirical AM1 method of HyperChem soft package. Results of studies on electronic structures and structure-relationship indicated that resemblance of global structures make them target to the same receptors, and difference of electronic structures led by difference of local structures make them target to differential subtypes of receptors. Based on the results, seven analogs of conotoxin GI were designed and calculated by quantum chemical method. Features of GI and analogs on the aspect of spatial structure and electronic structure were compared.

Key words: α-conotoxins, Nicotinic acetylcholine receptor, Electronic structure, Structure-activity relationship, Molecular design