基于网络药理学与分子对接探讨Zedoarondiol治疗动脉粥样硬化跨内皮迁移的作用机制

Mechanism of Zedoarondiol in Treating Transendothelial Migration of Atherosclerosis Based on Network Pharmacology and Molecular Docking

目的:基于网络药理学与分子对接技术探讨莪术奥酮二醇(Zedoarondiol)治疗动脉粥样硬化跨内皮迁移(transendothelial migration of atherosclerosis,TEMA)的作用机制。方法:采用OMIM和GeneCards数据库检索TEMA的靶点。通过PharmMapper和Swiss Target Prediction数据库检索Zedoarondiol的作用靶点。利用Venny 2.1软件获取TEMA与Zedoarondiol的交集靶点,通过STRING数据库构建蛋白质-蛋白质相互作用(protein-protein interaction,PPI)网络。借助Network Analyzer插件对PPI网络进行拓扑分析,并根据Degree值筛选核心靶点。利用DAVID数据库进行基因本体(Gene Ontology,GO)和京都基因与基因组百科全书(Kyoto Encyclopedia of Genes and Genomes,KEGG)分析。最后,通过PyRx AutoDock Vina软件进行分子对接验证。结果:通过检索得到TEMA靶点1340个,Zedoarondiol靶点215个,两者的交集靶点58个。Zedoarondiol治疗TEMA的核心靶点包括原癌基因酪氨酸蛋白激酶Src(SRC)、磷脂酰肌醇3-激酶调节亚基1(phosphatidylinositol 3-kinase regulatory subunit 1,PIK3R1)、蛋白酪氨酸磷酸酶非受体型11(protein tyrosine phosphatase nonreceptor 11,PTPN11)等。GO分析结果主要包括肽基酪氨酸磷酸化、跨膜受体蛋白酪氨酸激酶信号通路、磷脂酰肌醇3-激酶的正向调节等。KEGG分析结果主要包括Ras信号通路、血脂和动脉粥样硬化、VEGF信号通路、PI3K-Akt信号通路等。分子对接结果显示,Zedoarondiol与核心靶点(PIK3R1、SRC、PTPN11)的结合能均小于-5 kcal·mol^(-1)。结论:Zedoarondiol可能通过调节Ras、VEGF、PI3K-Akt等信号通路,以及SRC、PIK3R1、PTPN11等靶点,从而发挥治疗TEMA的作用。

Objective:To explore the mechanism of Zedoarondiol in treating transendothelial migration of atherosclerosis(TEMA)based on network pharmacology and molecular docking technology.Methods:The targets of TEMA were searched through OMIM and GeneCards databases.The targets of Zedoarondiol were searched through PharmMapper and Swiss Target Prediction databases.Intersected targets of TEMA and Zedoarondiol were collected using Venny 2.1 software,and protein-protein interaction(PPI)network was constructed through the STRING database.The Network Analyzer plug-in was used to analyze the topology of the PPI network,and the core targets were screened according to the Degree value.DAVID database was used for Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)analysis(P<0.05,Q<0.05).Finally,molecular docking verification was performed by PyRx AutoDock Vina software.Results:A total of 1340 targets of TEMA,215 targets of Zedoarondiol and 58 intersection targets of the two were identified.The core targets of Zedoarondiol in the treatment of TEMA include proto-oncogene tyrosine protein kinase Src(SRC),phosphatidylinositol 3-kinase regulatory subunit 1(PIK3R1),protein tyrosine phosphatase nonreceptor 11(PTPN11),etc.GO analysis mainly showed peptidyl-tyrosine phosphorylation,transmembrane receptor protein tyrosine kinase signaling pathway,and positive regulation of phosphatidylinositol 3-kinase.KEGG analysis results mainly include Ras signaling pathway,lipid and atherosclerosis,VEGF signaling pathway,PI3K-Akt signaling pathway and so on.According to the results of molecular docking,the binding energy of Zedoarondiol and core targets(PIK3R1,SRC,PTPN11)is less than-5 kcal/mol.Conclusion:Zedoarondiol may exert its therapeutic effect on TEMA by regulating the Ras,VEGF,PI3K-Akt signaling pathways and targets such as SRC,PIK3R1 and PTPN11.