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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 receprorα,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。
Synergistic effect is the main mechanism of Chinese medicine to play a pharmacodynamic effect, combined with the key target combination to explore the synergistic effect of Chinese medicine is to explain the synergistic mechanism of traditional Chinese medicine is one of the effective ways. Peptide transporter 1 (PepT1) is one of the key targets of drug absorption into blood, accounting for about 50% of the total transporter protein. Peroxisome proliferator-activated receptor alpha (PPARα) is a target of fibrate lipid-lowering drugs, and its agonists have good hypolipidemic efficacy. Studies have shown that PPARα can transactivate PepT1 gene expression, PPARα agonist can promote the absorption of PepT1 substrate, which together play a synergistic effect. Therefore, based on the target combination of PepT1 and PPARα, this study found the PepT1 substrate and PPARα agonist in the active ingredients of traditional Chinese medicine, and to explore the synergistic mechanism of active ingredients of Chinese traditional medicine to absorb blood and reduce blood lipid to a certain extent. This study was based on the fusion pharmacophore model of PPARα agonists that had been constructed in previous laboratories to screen potential Chinese herbal active ingredients with PPARα agonistic effects and to trace the origin of traditional Chinese medicines. At the same time, a support vector machine model of PepT1 substrate was constructed to predict the potential PepT1 substrate in traditional Chinese medicine. By analyzing the results of two groups, it was found that the combination of Panax notoginseng, Ganoderma lucidum, Panax notoginseng and Salvia miltiorrhiza could exert its lipid-lowering efficacy through the synergistic mechanism of PepT1 and PPARα. This study, based on the target combination of PepT1-PPARα, explores the synergistic mechanism of absorption and lipid-lowering efficacy of active ingredients of traditional Chinese medicine, and provides a new idea for the study of the synergistic mechanism of pharmacokinetic participation of traditional Chinese medicine based on target combination.