基于网络药理学与分子对接技术探索麦味地黄丸对特发性肺纤维化和2型糖尿病“异病同治”的作用机制

Mechanism of Maiwei Dihuang Pills in Treating Idiopathic Pulmonary Fibrosis and Type 2 Diabetes Mellitus with “Treating Different Diseases with Same Method” Based on Network Pharmacology and Molecular Docking Technology

摘要: 目的：基于“异病同治”的中医经典理论，运用网络药理学及分子对接技术探讨麦味地黄丸对特发性肺纤维化和2型糖尿病的关键分子机制。方法：利用中药复方以及中药材的各大数据库和分析平台数据库(TCMSP, TCM, BATMAN-TCM)筛选麦味地黄丸的活性成分，在OMIM、TTD、DrugBank、GeneCards、pahmGKB数据库平台预测IPF及T2DM疾病作用靶点。对麦味地黄丸活性成分靶点与麦味地黄丸、IPF及T2DM疾病交集靶点进行蛋白质互作(PPI)网络构建及核心靶点筛选，将筛选出的核心靶点进行GO和KEGG通路富集分析。筛选核心成分和核心靶点，利用Pubchem数据库、AutoDock软件、Discovery Studio软件等进行分子对接验证。结果：从麦味地黄丸中共筛选得到活性成分184个，活性成分潜在作用靶点1446个，取IPF疾病靶点前1555个，T2DM疾病靶点前1559个，取交集，获得麦味地黄丸-IPF-T2DM交集靶点238个。GO富集分析结果显示主要与骨髓细胞分化的正向调节、造血调节、破骨细胞分化、骨髓细胞分化的调节、正向调节生长、RNA聚合酶II转录、白细胞分化、对肽激素的反应、对肽的反应、细胞对生长因子刺激的反应等相关；KEGG通路富集分析得到131条通路，与IPF及T2DM相关且排序较靠前的通路有PD-L1表达和PD-1检查点通路在癌症中的应用、Th1和Th2细胞分化、Th17细胞分化等。分子对接结果表明，麦味地黄丸中的核心成分Aristolone (马兜铃酮)、Nootkatone (诺卡酮)、Quercetin (槲皮素)与核心靶点STAT1、FOS、IL2、CREB1、EGFR和MAPK14具有良好的结合潜力。结论：麦味地黄丸治疗IPF和T2DM具有多靶点效应，涉及多条生物过程和信号通路，可能通过调控PD-L1表达和PD-1检查点通路在癌症中的应用、Th1和Th2细胞分化、Th17细胞分化等通过炎症反应以及免疫调节发挥“异病同治”作用。

Abstract: Objective: Based on the classical theory of traditional Chinese medicine of “simultaneous treat-ment of different diseases”, the key molecular mechanism of Maiwei Dihuang Pill on idiopathic pulmonary fibrosis and type 2 diabetes mellitus was investigated by using network pharmacology and molecular docking technology. Methods: The active ingredients of Wheat Huang Pill were screened by using the Chinese medicine compound and the major databases and analysis platform databases of Chinese medicinal materials (TCMSP, TCM, BATMAN-TCM), and the target of IPF and T2DM diseases was predicted on the OMIM, TTD, DrugBank, GeneCards, and pahmGKB database platforms. The protein interaction (PPI) network construction and core target screening of the active ingredient target of Maiwei Dihuang Pills and the disease targets of Maiwei Dihuang Pills, IPF and T2DM were carried out, and perform GO and KEGG pathway enrichment analysis. Core components and core targets were screened, and molecular docking verification was carried out by using Pubchem database, AutoDock software, Discovery Studio software, etc. Results:A total of 184 active ingredients were screened from Maiwei Dihuang Pills, 1446 potential targets of active ingredients, 1555 first IPF disease targets and 1559 T2DM disease targets were taken and intersected, and 238 intersection targets of Maiwei Dihuang Pills-IPF-T2DM were obtained. The results of GO enrichment analysis showed that it was mainly related to the positive regulation of bone marrow cell differentiation, hematopoietic regulation, osteoclast differentiation, regulation of bone marrow cell differentiation, forward regulation of growth, RNA polymerase II transcription, leukocyte differentiation, response to peptide hormone, response to peptide, and cell response to growth factor stimulation. KEGG pathway enrichment analysis yielded 131 pathways, including PD-L1 expression and PD-1 checkpoint pathway in cancer, differentiation of Th1 and Th2 cells, and differentiation of Th17 cells. The results of molecular docking showed that the core components Aristolone, Nootkatone and Quercetin in Maiwei Dihuang Pills had good binding potential with the core targets STAT1, FOS, IL2, CREB1, EGFR and MAPK14. Conclusion: The treatment of IPF and T2DM has multi-target effects, involving multiple biological processes and signaling pathways, which may play a role in “treating different diseases” through inflammatory response and immune regulation by regulating PD-L1 expression and PD-1 checkpoint pathway in cancer, Th1 and Th2 cell differentiation, Th17 cell differentiation, etc.