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六氢嘧啶-5-醇类新型非肽类β-分泌酶抑制剂的基于结构的药物分子设计

周博, 牛彦, 邹晓民, 许凤荣, 袁悦, 王超, 高海飞, 刘鹏, 徐萍*   

  1. 北京大学医学部 药学院 药物化学系, 北京 100191
  • 收稿日期:2010-05-25 修回日期:2010-08-10 出版日期:2010-09-20 发布日期:2010-09-20
  • 通讯作者: 徐萍*

Structure-based design of hexahydropyrimidin-5-ols as novel non-peptidic β-secretase inhibitors

Bo Zhou, Yan Niu, Xiao-Min Zou, Feng-Rong Xu, Yue Yuan, Chao Wang, Hai-Fei Gao, Peng Liu, Ping Xu*   

  1. Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China
  • Received:2010-05-25 Revised:2010-08-10 Online:2010-09-20 Published:2010-09-20
  • Contact: Ping Xu*

摘要: 本文由文献报道的已知小分子苗头化合物片段出发, 基于其与β-分泌酶结合的晶体结构, 通过结构修饰设计了全新的非肽类小分子β-分泌酶抑制剂: 六氢嘧啶-5-醇系列及其两类类似物系列。计算机辅助药物设计的研究得到了良好的结果。我们测试了各类母核的β-分泌酶抑制活性, 结果进一步支持了我们的设计思路。

关键词: β-分泌酶抑制剂, 六氢嘧啶-5-醇类, 基于结构的药物分子设计, 计算机辅助药物设计

Abstract:

Based upon the crystal structure of a previously reported fragment hit that binds to β-secretase, a novel series of non-peptidic small-molecule β-secretase inhibitors, namely hexahydropyrimidin-5-ols, along with two series of their analogues, were rationally designed through structural modification. The CADD study was performed and revealed good expectation. Inhibitory activities of the corresponding structural cores were tested, which provided further support for our design approach.

Key words: β-Secretase inhibitors, Hexahydropyrimidin-5-ols, Structure-based drug design, Computer-aided drug design

中图分类号: 

Supporting:

Foundation items: National Natural Science Foundation of China (Grant No. 20772008 and 30772650).
*Corresponding author. Tel.: 86-10-82801505