Mechanism of Caffeoylquinic Acids in the Treatment of Type II Diabetes Based on Network Pharmacology
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摘要: 目的：基于网络药理学方法分析咖啡酰奎宁酸类化合物治疗II型糖尿病的作用机制。方法：通过文献挖掘和数据库检索获取咖啡酰奎宁酸类化合物作用靶点以及与II型糖尿病相关的疾病靶点，绘制咖啡酰奎宁酸类化合物的“成分-疾病-靶点”功效作用网络，对其进行基因本体论（GO）分析和京都基因与基因组百科全书（KEGG）通路分析，并将核心靶点蛋白与关键成分进行分子对接验证。结果：咖啡酰奎宁酸类化合物对应靶点483个，II型糖尿病相关靶点2214个，交集靶点211个，关键靶点37个。咖啡酰奎宁酸类化合物治疗II型糖尿病的作用机制主要涉及细胞外基质降解、基质金属蛋白酶的激活、胶原蛋白降解等多条通路，主要涉及AKT1、MMP3、MMP9、HIF1A、IGF1R、MAPK8等基因，这些基因主要通过调控葡萄糖代谢以及调节相关蛋白质发挥作用。化合物与分子靶点对接结果良好，验证了网络构建预测的准确性。结论：本研究预测了咖啡酰奎宁酸类化合物治疗II型糖尿病的关键靶点与作用机制，为深入开展咖啡酰奎宁酸类化合物治疗II型糖尿病的分子机制研究提供了科学依据。
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关键词:
- 网络药理学 /
- 咖啡酰奎宁酸类化合物 /
- II型糖尿病 /
- 作用机制
Abstract: Objective: Analyzing the mechanism of type II diabetes treatment with caffeoylquinic acids based on network pharmacology. Methods: Through literature mining and database search, the target points of caffeoylquinic acids and disease targets related to type II diabetes were obtained. The “component-disease-target” effect network of caffeoylquinic acids was drawn, and gene ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genome (KEGG) pathway analysis were carried out. The core target proteins and key components were used for the molecular docking verification. Results: Caffeoylquinic acids corresponded to 483 targets, 2214 type II diabetes-related targets, 211 common targets, and 37 key targets. The mechanism of action of caffeoylquinic acids in the treatment of type II diabetes mainly involved multiple pathways such as degradation of the extracellular matrix, activation of matrix metalloproteinases, collagen degradation, etc. It mainly involved AKT1, MMP3, MMP9, HIF1A, IGF1R, MAPK8 and other genes, these genes were usually reported to play a role mainly by regulating glucose metabolism and related proteins. The results of molecular docking verification between compounds and molecular targets were good, which verified the accuracy of the prediction of network construction. Conclusion: This study predicted the key targets and mechanism of action of caffeoylquinic acids to treat type II diabetes. It also provided a scientific basis for further research on the molecular mechanism of caffeoylquinic acids in the treatment of type II diabetes.-
Key words:
- network pharmacology /
- caffeoylquinic acids /
- type II diabetes /
- mechanism of action
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图 2 咖啡酰奎宁酸类化合物治疗II型糖尿病的关键靶点网络
Figure 2. Key target network of caffeoylquinic acids in the treatment of type II diabetes
图 3 咖啡酰奎宁酸类化合物治疗II型糖尿病的关键靶点GO分析
Figure 3. GO analysis of key targets of caffeoylquinic acids in the treatment of type II diabetes
图 4 咖啡酰奎宁酸类化合物治疗II型糖尿病的关键靶点KEGG通路富集分析
Figure 4. KEGG pathway enrichment analysis of key targets of caffeoylquinic acids in the treatment of type II diabetes
图 5 咖啡酰奎宁酸类化合物治疗II型糖尿病的作用通路与其相关靶点网络分析
Figure 5. Network analysis of the pathways of caffeoylquinic acids in the treatment of type II diabetes and their related targets
图 6 IGF1R、JAK1、RPS6KB1与3个关键成分的最佳对接构象
Figure 6. Optimal docking conformation of IGF1R, JAK1, RPS6KB1 and the three key components
注：(a). IGF1R与绿原酸的最佳对接构象；(b). JAK1与异绿原酸A的最佳对接构象；(c). RPS6KB1与1,3,5-O-三咖啡酰奎宁酸的最佳对接构象。
表 1 咖啡酰奎宁酸类化合物治疗II型糖尿病的37个关键靶点信息表
Table 1. 37 key targets information table of caffeoylquinic acids in the treatment of type II diabetes
编号 目标基因 目标蛋白质 靶向蛋白的生物学活性 1 IGF1R Insulin-like growth factor 1 receptor 介导胰岛素样生长因子1 2 JAK1 Tyrosine-protein kinase JAK1 细胞因子信号传导过程 3 RPS6K B1 Ribosomal protein S6 kinase beta-1 调控细胞增殖、细胞生长和细胞周期 4 MA PK8 Mitogen-activated protein kinase 8 调控细胞增殖、分化及迁移 5 MTOR Serine/threonine-protein kinase mTOR 调节蛋白质的磷酸化 6 JAK2 Tyrosine-protein kinase JAK2 参与细胞生长、发育、分化及组蛋白修饰 7 HSP90AA1 Heat shock protein HSP 90-alpha 参与细胞周期调控及信号传导过程 8 PTPRC Receptor-type tyrosine-protein phosphatase C 参与细胞生长、分化及有丝分裂等 9 SIRT1 NAD-dependent protein deacetylase sirtuin-1 诱导线粒体生物合成，抗炎和防止代谢下降 10 MCL1 Induced myeloid leukemia cell differentiation protein Mcl-1 参与调控细胞凋亡及细胞存活 11 MET Hepatocyte growth factor receptor 调控细胞生长、生存、侵袭及转移等 12 HSPA5 78 kDa glucose-regulated protein 促进蛋白质多聚体组装 13 ERBB2 Receptor tyrosine-protein kinase erbB-2 介导细胞信号转导过程 14 MMP7 Matrilysin 降解细胞外基质 15 ALB Serum albumin 调节血浆pH和维持血浆渗透压 16 SRC Proto-oncogene tyrosine-protein kinase Src 编码酪氨酸蛋白激酶 17 IL2 Interleukin-2 调节免疫反应 18 MMP3 Stromelysin-1 降解纤连蛋白 19 MAPK3 Mitogen-activated protein kinase 3 调控细胞生长、存活及分化 20 MAPK1 Mitogen-activated protein kinase 1 调控细胞生长、存活及分化 21 EP300 Histone acetyltransferase p300 转录调节 22 MMP2 72 kDa type IV collagenase 降解多种细胞外基质 23 PLAU Urokinase-type plasminogen activator 参与细胞外基质的降解 24 MAPK14 Mitogen-activated protein kinase 14 参与细胞增殖、分化、转录调控等过程 25 HIF1A Hypoxia-inducible factor 1-alpha 转录调节 26 EGFR Epidermal growth factor receptor 调控细胞的生长和分化 27 MMP1 Interstitial collagenase 降解细胞外基质 28 PARP1 Poly [ADP-ribose] polymerase 1 调控细胞的增殖、分化及凋亡 29 AKT1 RAC-alpha serine/threonine-protein kinase 调控葡萄糖代谢 30 CASP3 Caspase-3 调控细胞凋亡 31 CXCR4 C-X-C chemokine receptor type 4 降低的细胞cAMP水平 32 CASP8 Caspase-8 调控细胞凋亡 33 ESR1 Estrogen receptor 调控细胞增殖和分化 34 VEGFA Vascular endothelial growth factor A 诱导内皮细胞增殖、促进内皮细胞迁移并抑制内皮细胞凋亡 35 PLG Plasminogen 调控细胞增殖 36 MMP9 Matrix metalloproteinase-9 调控细胞外基质的局部蛋白水解和白细胞迁移 37 TNF Tumor necrosis factor 调控细胞的增殖与分化 
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表 2 KEGG通路富集分析相关基因
Table 2. Related genes for KEGG pathway enrichment analysis
通路名称 相关基因 P-Value值 基因数 Intrinsic pathway for apoptosis AKT1, CASP3 , CASP8, MAPK8 1.4129E-05 4 MAPK3 (ERK1) activation JAK1 , JAK2, MAPK3 4.63558E-06 3 RAF-independent MAPK1/3 activation JAK1, JAK2, MAPK1, MAPK3 1.06568E-06 4 MAPK1 (ERK2) activation JAK1, JAK2, MAPK1 3.25274E-06 3 GPVI-mediated activation cascade AKT1, IL-2, JAK1, JAK2 4.07089E-05 4 Signaling by ERBB2 AKT1, EGFR, erb-B2, HSP90AA1, SRC 7.4417E-07 5 Regulation of gene expression by Hypoxia-inducible Factor EP300, HIF-1 α, VEGF-A 6.35858E-06 3 Regulation of Hypoxia-inducible Factor (HIF) by oxygen EP300, HIF-1α, VEGF-A 0.002231183 3 Spry regulation of FGF signaling MAPK1, MAPK3, SRC 2.13221E-05 3 Signaling by SCF-KIT JAK2, MMP9, SRC 0.000440327 3 Collagen degradation MMP1, MMP2, MMP3, MMP7, MMP9 2.58498E-06 5 Degradation of the extracellular matrix CASP3, MMP1, MMP2, MMP3, MMP7, MMP9, PLG 4.28006E-07 7 Activation of Matrix Metalloproteinases MMP1, MMP2, MMP3, MMP7, MMP9, PLG 1.23119E-09 6 mTOR signalling AKT1, mTOR, RPS6Kb1 0.000382181 3 Activated TLR4 signalling CASP8, MAPK1, MAPK14, MAPK3, MAPK8 5.17597E-05 5 MyD88: Mal cascade initiated on plasma membrane MAPK1, MAPK14, MAPK3, MAPK8 0.000346725 4 MyD88-independent TLR4 cascade CASP8, MAPK1, MAPK14, MAPK3, MAPK8 2.5656E-05 5 Toll Like Receptor 9 (TLR9) Cascade MAPK1, MAPK14, MAPK3, MAPK8 0.000389474 4 Toll Like Receptor 10 (TLR10) Cascade MAPK1, MAPK14, MAPK3, MAPK8 0.000228363 4 Toll Like Receptor 3 (TLR3) Cascade CASP8, MAPK1, MAPK14, MAPK3, MAPK8 2.446E-05 5
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表 3 3个靶点与3个关键成分的分子对接得分
Table 3. Molecular docking scores of 3 targets and 3 key components
化合物 蛋白质 PDB ID 结合能（kcal/mol） RMSD 绿原酸 IGF1R 2oJ9 −9.2 0.645 JAK1 5e1e −9.1 1.672 RPS6KB1 4l3j −8.3 0.967 异绿原酸A IGF1R 2oJ9 −9.0 1.367 JAK1 5e1e −10.0 1.306 RPS6KB1 4l3j −9.9 0.772 1,3,5-O-三咖啡酰奎宁酸 IGF1R 2oJ9 −9.1 1.304 JAK1 5e1e −9.7 1.476 RPS6KB1 4l3j −10.3 1.811
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