基于网络药理学和分子对接技术研究升陷汤“异病同治”特发性肺纤维化和哮喘的作用机制

Network Pharmacology and Molecular Docking Techniques to Research the Mechanism of Action of Sheng Xian Tang in Treating Idiopathic Pulmonary Fibrosis and Asthma by “Treating Different Diseases Together”

摘要: 背景：由于IPF和asthma临床上尚无有显著效果的药物，且预后差，迫切需要确定更安全、更有效的药物。而随着中医药的不断发展，中药治疗IPF和asthma的研究也在不断开展，升陷汤作为一个经典名方，主治“大气下陷”之症，因此可以研究“异病同治”IPF和asthma的机理。目的：采用网络药理学和分子对接技术来探究升陷汤“异病同治”IPF和asthma的作用机制。方法：利用TCMSP数据库及Batman-TCM数据库筛选升陷汤方中黄芪、知母、柴胡、桔梗、升麻的成分和对应的靶点；从GeneCards、DrugBank、Disgenet、OMIM以及TTD五个疾病数据库分别筛选IPF和asthma的相关靶点；在venny平台获取药物和疾病的交集靶点；通过STRING数据库和Cytospace 3.7.2软件，建立蛋白相互作用网络。将交集靶点导入DAVID数据库进行GO功能富集和KEGG信号通路分析，并绘制“成分–靶点–通路”网络图；利用Cytoscape 3.7.2，构建“化学成分–共同靶点–疾病”的相互作用网络；筛选出具有较高药效的有效化学成分与该病的关键靶点进行分子对接。结果升陷汤中含有158个化学成分，1754个靶点；IPF靶点1937个，asthma靶点2034个；升陷汤与IPF以及asthma的交集靶点共有247个；蛋白质相互作用网络中排名靠前的靶点有STAT3、SRC、JUN、EP300、PIK3CA、MAPK3、MAPK1、TP53、AKT1和HSP90AA1等；其中重要的信号通路主要有AGE-RAGE信号通路、癌症信号通路、TNF信号通路等；升陷汤中的关键活性成分有槲皮素、山奈酚、豆甾醇等；分子对接分析表明，槲皮素-JUN、豆甾醇-MAPK1、木犀草素-MAPK1、豆甾醇-MAPK3等多组数据结合能均小于−7，结合效果良好，对接构象稳定。结论：升陷汤治疗IPF和asthma可能主要涉及到STAT3、SRC、JUN、EP300、PIK3CA等核心靶点，通过药物的关键活性成分来调节多个靶点、多条通路、多个生物过程达到“异病同治”IPF和asthma的作用。

Abstract: Background: due to the lack of clinically effective drugs for IPF and asthma and the poor prognosis, there is a pressing need to identify safer and more effective drugs. With the continuous development of conventional Chinese medicine reseach on the treatment of IPF and asthma with traditional Chinese medicine are also being carried out. Sheng Xian Tang, as a classic prescription, is used to treat the disease of “atmospheric subsidence”, so the mechanism of treating IPF and asthma with different diseases can be studied. Objective: To explore the mechanism of action of Sheng Xian Tang “treating different diseases together” IPF and asthma by adopting network pharmacology and molecular docking techniques. Methods: TCMSP database and Batmand-TCM database were utilized to filter out the constituents and corresponding targets of Huang Qi, Zhi Mu, Chai Hu, Jie Geng and Sheng Ma in Sheng Xian Tang recipe. Targets related to IPF and asthma were screened from GeneCards, DrugBank, Disgenet, OMIM and TTD. The intersection targets between drugs and disease was acquired on venny platform. The protein interaction network was constructed through STRING database and Cytospace 3.7.2 software. The intersection targets were imported into DAVID database for GO function enrichment and KEGG signal pathway analysis, and the “component-target-pathway” network map was drawn. The interaction network of chemical composition, common target and disease was constructed using Cytoscape 3.7.2. The effective chemical components with high values were screened for molecular docking with the key targets of the disease. Results There were 158 chemical constituents and 1754 targets in Sheng Xian Tang. There were 1937 IPF targets and 2034 asthma targets; there are 247 intersection targets of Sheng Xian Tang, IPF and asthma. The top targets in the protein interaction network were STAT3, SRC, JUN, EP300, PIK3CA, MAPK3, MAPK1, TP53, AKT1 and HSP90AA1. The important signaling pathways includeAGE-RAGE signaling pathway, cancer signaling pathway, TNF signaling pathway, etc. The key active ingredients in Sheng Xian Tang were quercetin, kaempferol, stigmasterol, etc. Mo-lecular docking analysis showed that the binding energy of quercetin-Jun, stigmasterol-MAPK1, luteolin-MAPK1, stigmasterol-MAPK3 was lower than −7, and the binding effect was good and the docking conformation was stable. Conclusions: Sheng Xian Tang in the treatment of IPF and asthma may mainly involve core targets such as STAT3, SRC, JUN, EP300, PIK3CA, etc. Through the key active ingredients of drugs to regulate multiple targets, multiple pathways, multiple biological processes to achieve the effect of “treating different diseases together” IPF and asthma.