中国中药杂志

2015, v.40(15) 3063-3067

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基于受体药效团的CETP天然抑制剂的发现研究
Virtual screening for natural CETP inhibitors by structure-based pharmacophore

霍晓乾;乔连生;蒋芦荻;贺昱甦;李贡宇;张燕玲;
HUO Xiao-qian;QIAO Lian-sheng;JIANG Lu-di;HE Yu-su;LI Gong-yu;ZHANG Yan-ling;Beijing University of Chinese Medicine,Research Center of Traditional Chinese Medicine-information Engineering;

摘要(Abstract):

胆固醇酯转移蛋白(cholesterol ester transfer protein,CETP)是HDL的重要调控因子,抑制其活性可有效提高HDL的含量。由于HDL通过胆固醇逆向转运对动脉粥样硬化发挥的重要遏制作用,CETP已成为治疗心血管疾病的热门靶点。该文以PDB数据库中编号为4F2A的CETP蛋白结构为研究对象,对其活性区域内的药效特征进行识别、聚类及筛选,建立了基于CETP蛋白结构的受体药效团。最优药效团由6个疏水特征、1个氢键供体特征及9个排除体积组成,其辨识有效性指数N为3.33,综合评价指数CAI为2.31。同时,利用该模型对TCMD进行虚拟筛选,获得来源于315味中药的629个化合物。最后,该研究基于分子对接技术探讨了活性区域的关键氨基酸残基以及中药活性化合物与受体的相互作用,进一步验证了研究结果的可靠性。其中枸杞子、五味子等部分含有潜在活性成分较多的中药已有文献报道确有降脂活性。该研究为从中药中发现CETP抑制剂、探讨中药降脂作用机制提供了数据支撑。
Cholesterol ester transfer protein( CETP) is a key regulator of high density lipoprotein( HDL). Owing to its important role in the reverse of cholesterol transport,CETP has become a hotspot target in modulating lipid drug design. In this paper,structure based pharmacophore( SBP) models for CETP inhibitors were built based on the protein structure 4F2 A from Protein Database( PDB).The best pharmacophore contained six hydrophobic features,one hydrogen bond acceptor feature and nine excluded volume features,with the N and CAI value was 3. 33 and 2. 31 respectively. Then the model was used to search the traditional Chinese medicine database( TCMD) and 629 compounds originated from 315 TCM herbs were obtained. Molecular docking was also used to validate SBP by analyzing the critical amino acid residue and the interaction between potential active compounds and receptor. In this study,several TCM herbs,like Lycii Frutus and Schisandrae chinensis fructus,which contained more optimal SBP based screening results,have been reported hypolipidemic effect,and need to be studied deeply in a more focused research on herbal active constituents. Therefore,this study could provide reliable fundamental data for exploring the action mechanisms of TCM,and be applicable to identify lead candidates,which can be utilized as starting scaffolds for natural CETP inhibitors.

关键词(KeyWords): 降血脂;胆固醇酯转移蛋白;受体药效团;分子对接;虚拟筛选
lipid-lowering;CETP;SBP;molecular docking;virtual screening

Abstract:

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基金项目(Foundation): 国家自然科学基金项目(81173522);; 北京市与中央在京高校共建项目(BJGJ1412)

作者(Author): 霍晓乾;乔连生;蒋芦荻;贺昱甦;李贡宇;张燕玲;
HUO Xiao-qian;QIAO Lian-sheng;JIANG Lu-di;HE Yu-su;LI Gong-yu;ZHANG Yan-ling;Beijing University of Chinese Medicine,Research Center of Traditional Chinese Medicine-information Engineering;

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