新型CDK2-cyclinA2小分子抑制剂的设计、合成及生物学活性研究

目的·设计、合成新型CDK2-cyclin A2小分子抑制剂并探讨此类抑制剂的构效关系。方法·通过计算机辅助药物设计方法,以CDK2-cyclin A2晶体ATP结合区域为口袋,筛选出先导化合物。根据CDK2-cyclin A2的ATP结合区域特点,设计合成一系列苯磺酰胺类化合物;根据已构建好的体外激酶活性检测体系,对化合物体外活性进行研究。结果·合成了29个新型苯磺酰胺类CDK2-cyclin A2抑制剂,化合物对CDK2-cyclin A2抑制检测结果显示,WZ-026对CDK2-cyclin A2抑制作用的IC50值为3.81μmol/L。结论·综合虚拟筛选、化学合成、生物检测等方法,得...

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Published in上海交通大学学报（医学版） Vol. 37; no. 3; pp. 330 - 336
Main Author 卫迎庆 张璐 胡雨彤 张健 沈瑛
Format Journal Article
LanguageChinese
Published 上海交通大学基础医学院,上海,200025%大连医科大学药学院,大连,116044 2017
Subjects
A2
CDK2-cyclin
抑制剂
构效关系
细胞周期
细胞周期
抑制剂
inhibitor
cell cycle
构效关系
structure-activity relationship
CDK2-cyclinA2
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Summary:目的·设计、合成新型CDK2-cyclin A2小分子抑制剂并探讨此类抑制剂的构效关系。方法·通过计算机辅助药物设计方法,以CDK2-cyclin A2晶体ATP结合区域为口袋,筛选出先导化合物。根据CDK2-cyclin A2的ATP结合区域特点,设计合成一系列苯磺酰胺类化合物;根据已构建好的体外激酶活性检测体系,对化合物体外活性进行研究。结果·合成了29个新型苯磺酰胺类CDK2-cyclin A2抑制剂,化合物对CDK2-cyclin A2抑制检测结果显示,WZ-026对CDK2-cyclin A2抑制作用的IC50值为3.81μmol/L。结论·综合虚拟筛选、化学合成、生物检测等方法,得到对CDK2-cyclin A2有明显抑制活性的苯环酰胺类化合物WZ-026;初步得到此类小分子化合物与CDK2-cyclin A2的作用模式。
Bibliography:WEI Ying-qing1, ZHANG Lu2, HU Yu-tong1, ZHANG Jian1, SHEN Ying1（1. Basic Medicine Faculty of Shanghai Jiao Tong University, Shanghai 200025, China; 2. College of Pharmacy, Dalian Medical University, Dalian 116044, China）
31-2045/R
Objective · To design and synthesize a series of benzenesulfonamide derivatives, test their inhibitory activity to CDK2-cyclinA2 kinase, and investigate the structure-activity relationship. Methods · Virtual screening was executed via computer-aided drug design according to the ATP binding site in CDK2-cyclinA2 protein crystal. A series of benzenesulfonamide derivatives were designed and synthesized on the basis of the interaction modes between the lead compound and the CDK2-cyclinA2. The biological evaluation of compounds was made through the CDK2-cyclinA2 in-vitro kinase activity detection system. Results · Twenty-nine new benzenesulfonamide compounds were prepared, and their inhibitory activity to CDK2-cyclinA2 was elicited. WZ-026 had the highest inhibitory parameter, which half m
ISSN:1674-8115
DOI:10.3969/j.issn.1674-8115.2017.03.010