张景芳;李彦程;夏桂阳;宋云清;王玲燕;林鹏程;葛广波;林生;
ZHANG Jing-fang;LI Yan-cheng;XIA Gui-yang;SONG Yun-qing;WANG Ling-yan;LIN Peng-cheng;GE Guang-bo;LIN Sheng;State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College;Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine;College of Pharmaceutical Sciences, Qinghai University for Nationalities;

• 1:中国医学科学院北京协和医学院药物研究所天然药物活性物质与功能国家重点实验室
• 2:上海中医药大学交叉科学研究院
• 3:青海民族大学药学院

摘要(Abstract)：

该文通过收集文献中已报道的人羧酸酯酶2(human carboxylesterase 2,hCE2)小分子抑制剂,选择其中活性较强的化合物作为训练集,利用HipHop方法建立hCE2抑制剂的三维药效团模型。结果表明最优药效团具有2个疏水中心、1个氢键受体和1个芳环中心。利用测试集对其进行验证,准确率达95%以上。在此基础上,将该预测模型用于hCE2天然抑制剂的虚拟筛选,从赤芍化学成分中发现了5个hCE2的天然抑制剂,并对其hCE2抑制能力进行了实验验证。结果显示5个赤芍化学成分(CS-1,CS-2,CS-3,CS-6和CS-8)对hCE2的IC_(50)分别5.04,5.21,5.95,6.64,7.94μmol·L~(-1),提示该研究构建的药效团模型具有较好的预测能力,有助于发现新型的hCE2抑制剂。
According to human carboxylesterase 2(hCE2) inhibitors reported in the literature, the pharmacophore model of hCE2 inhibitors was developed using HipHop module in Discovery Studio 2016. The optimized pharmacophore model, which was validated by test set, contained two hydrophobic, one hydrogen bond acceptor, and one aromatic ring features. Using the pharmacophore model established, 5 potential hCE2 inhibitors(CS-1,CS-2,CS-3,CS-6 and CS-8) were screened from 20 compounds isolated from the roots of Paeonia lactiflora, which were further confirmed in vitro, with the IC_(50) values of 5.04, 5.21, 5.95, 6.64 and 7.94 μmol·L~(-1), respectively. The results demonstrated that the pharmacophore model exerted excellent forecasting ability with high precision, which could be applied to screen novel hCE2 inhibitors from Chinese medicinal materials.

关键词(KeyWords)： 药效团模型;人羧酸酯酶2;hCE2抑制剂;赤芍
pharmacophore model;human carboxylesterase 2;hCE2 inhibitors;Paeonia lactiflora

Abstract:

Keywords:

基金项目(Foundation): 国家自然科学基金项目(81773589,81522050,81760783);; 北京市自然科学基金项目(JQ18026);; 国家“重大新药创制”科技重大专项(2018ZX09711001-001-001,2018ZX09711001-001-003,2018ZX09711001-001-008);; 中国医学科学院医学与健康科技创新工程项目(2017-I2M-3-010);; 青海省基础研究计划项目(2018-ZJ-739);; 上海市科学技术委员会上海市优秀学术带头人计划项目(18XD1403600)

作者(Author): 张景芳;李彦程;夏桂阳;宋云清;王玲燕;林鹏程;葛广波;林生;
ZHANG Jing-fang;LI Yan-cheng;XIA Gui-yang;SONG Yun-qing;WANG Ling-yan;LIN Peng-cheng;GE Guang-bo;LIN Sheng;State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College;Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine;College of Pharmaceutical Sciences, Qinghai University for Nationalities;

Email:

DOI: 10.19540/j.cnki.cjcmm.20190603.203

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