上海交通大学学报（医学版）

上海交通大学学报（医学版）

• 论著（基础研究） • 上一篇    下一篇

CDK2别构小分子抑制剂的虚拟筛选和体外活性研究

邵媛媛1，张璐2，沈瑛1，张健1   

  1. 1.上海交通大学  基础医学院， 上海 200025； 2.大连医科大学  药学院， 大连 116044
  • 出版日期:2016-04-28 发布日期:2016-05-26
  • 通讯作者: 张健, 电子信箱: jian.zhang@sjtu.edu.cn。
  • 作者简介:邵媛媛（1991—）， 女， 硕士生; 电子信箱: soil1213@126.com。

Virtual screening of and in vitro activity study on allosteric small-molecule CDK2 inhibitors

SHAO Yuan-yuan1, ZHANG Lu2, SHEN Ying1, ZHANG Jian1   

  1. 1.Basic Medicine Faculty of Shanghai Jiao Tong University, Shanghai 200025, China; 2.College of Pharmacy, Dalian Medical University, Dalian 116044,  China
  • Online:2016-04-28 Published:2016-05-26

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1002

摘要：

目的 根据CDK2的晶体结构（PDB ID：3PXF），在已验证的别构口袋处，拟筛选出CDK2新型别构小分子抑制剂。方法 通过计算机辅助药物设计方法，基于CDK2蛋白晶体别构位点进行虚拟筛选，综合分析化合物与CDK2的作用模式；构建CDK2体外激酶活性检测体系，对化合物进行初步的体外生物活性研究。结果虚拟筛选得到打分前1 000名的化合物，最终挑选并购买10个候选化合物。其中，化合物S2和S5表现出较好的抑制效果，在100 μmol/L的浓度下对CDK2活性的抑制率分别为57.59%和41.64%。结论 综合利用虚拟筛选、结构分析以及生物活性测试，筛选出具有明显的CDK2抑制活性的先导化合物S2和S5，为设计开发新型的 CDK2别构小分子抑制剂奠定了基础。

关键词: CDK2, 细胞周期, 虚拟筛选, 别构抑制剂

Abstract:

Objective To screen out novel allosteric small-molecule CDK2 inhibitors in verified allosteric pocket based on the crystal structure of CDK2 (PDB ID: 3PXF). Methods Virtual screening was performed via computer-aided drug design according to the allosteric site in CDK2 protein crystal. The interaction modes between the compounds and CDK2 were comprehensively analyzed. The CDK2 in vitro kinase activity detection system was established and the in vitro bioactivity of the compounds was primarily studied. Results Top 1000 compounds were obtained by virtual screening and 10 of them were selected and purchased. Compounds S2 and S5 showed favorable inhibitory effect and their inhibitory rates against CDK2 at the concentration of 100 μmol/L were 57.59% and 41.64%, respectively. Conclusion By utilization of virtual screening, structural analysis, and biological activity test, two lead compounds S2 and S5 were screened out, which can significantly inhibit the activity of CDK2. This work lays a foundation for design and development of novel allosteric small-molecule CDK2 inhibitors.

Key words: CDK2, cell cycle, virtual screening, allosteric inhibitor