Qiao Lian-Sheng, Chen Yan-Kun, Luo Gang-Gang, Lu Fang, Liu Si-Jia, Li Gong-Yu, Zhang Yan-Ling
Key Laboratory of Traditional Chinese Medicine Foundation and New Drug Research, School of Chinese Material Medica, Beijing University of Chinese Medicine, Beijing 100102, China.
Zhongguo Zhong Yao Za Zhi. 2017 Jun;42(11):2146-2151. doi: 10.19540/j.cnki.cjcmm.2017.0096.
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 and Salvia miltiorrhiza were identified to have the synergistic mechanism based on target combination of PepT1 and PPARα. In this study, synergistic mechanism of TCM was analyzed for absorption and hypolipidemic effect based on target combination, which provides a new way to explore the synergetic mechanism of TCM related to pharmacokinetics.
协同效应是中药的主要药理机制。基于关键靶点组合的研究方法是探索中药协同效应的重要方法。肽转运体1（PepT1）是药物进入血液循环的关键靶点，约占小肠转运蛋白总量的50%。过氧化物酶体增殖物激活受体α（PPARα）是贝特类药物的降脂靶点，通过激活PPARα具有良好的降血脂作用。据报道，PPARα可激活PepT1的基因表达，PPARα激动剂可促进PepT1底物的摄取，表明它们具有协同效应。本文发现了来自中药的PepT1底物和PPARα激动剂，并基于PepT1与PPARα的靶点组合探讨了它们的协同机制。首先构建了PepT1底物的支持向量机（SVM）模型并用于预测潜在的中药成分。同时，利用PPARα激动剂的融合药效团和对接模型从中药中筛选潜在的活性成分。根据两组分析结果，确定三七与灵芝的中药组合以及三七与丹参的中药组合基于PepT1与PPARα的靶点组合具有协同机制。本研究基于靶点组合分析了中药在吸收和降血脂方面的协同机制，为探索中药与药代动力学相关的协同机制提供了新途径。
