基于PepT1―PPARα靶标组合中药协同机制解析.docVIP

基于PepT1―PPARα靶标组合中药协同机制解析 　　[摘要] 协同效应是中药发挥药效的主要作用机制，结合关键靶标组合探讨中药的协同效应是阐释中药协同机制的有效方法之一。寡肽转运蛋白（peptide transporter 1，PepT1）是药物吸收入血的关键靶标之一，约占总转运蛋白含量的50%。过氧化物酶体增殖物激活受体α（peroxisome proliferator-activated recepror α，PPARα）是贝特类降脂药物的作用靶点，其激动剂具有良好的降血脂药效。研究表明PPARα可反式激活PepT1的基因表达，PPARα激动剂可促进PepT1底物的吸收，从而共同发挥协同作用。因此，本研究拟基于PepT1和PPARα的靶标组合，发现中药活性成分中的PepT1底物和PPARα激动剂，并在一定程度上探讨中药活性成分吸收入血与降低血脂的协同机制。该研究基于前期实验室已构建的PPARα激动剂的融合药效团模型，筛选潜在的具有PPARα激动效应的中药活性成分，并追溯其来源中药。同时构建PepT1底物的支持向量机模型，预测中药中潜在的PepT1底物。通过分析2组筛选结果，发现三七-灵芝、三七-丹参组合可能通过PepT1和PPARα协同机制发挥降脂药效。该研究基于PepT1-PPARα的靶标组合，探索中药活性成分吸收与降脂药效的协同机制，为基于靶标组合探讨中药药代动力学参与的协同机制研究提供了一条新思路。 　　[关键词] PepT1；PPARα；协同机制；SVM；融合药效团；分子对接；虚拟筛选 　　[Abstract] Synergistic effect is main pharmacological mechanism of traditional Chinese medicine（TCM）. The research method based on the key targets combination is an important method to explore the synergistic effect of TCM. Peptide transporter 1 （PepT1） is an essential target for drug uptake into the bloodstream，accounting for about 50% of the total transporter protein content from the small intestine. Peroxisome proliferator-activated receptor α（PPARα） is the lipid-lowering target of fibrates，which have a good hypolipidemic effect by activating PPARα. It has been reported that PPARα could activate the gene expression of PepT1s，and PPARα agonists can promote the uptake of PepT1 substrates，indicating their synergistic effect. In this paper，PepT1 substrates and PPARα agonists from TCM were discovered，and their synergistic mechanism was also been discussed based on the target combination of PepT1 and PPARα. The support vector machine（SVM） model of PepT1 substrates was first constructed and utilized to predict potential TCM components. Meanwhile，merged pharmacophore and docking model of PPARα agonists was used to screen the potential active ingredients from TCM. According to the analysis results of two groups，the TCM combination of Panax notoginseng and Ganoderma lucidum，as well as TCM combination of P. notoginseng