基于网络药理学和分子对接的四妙散治疗糖尿病周围神经病变机制研究

Study on the Mechanism of Simiaosan in the Treatment of Diabetic Peripheral Neuropathy Based on Network Pharmacology and Molecular Docking

目的:利用网络药理学和分子对接技术对四妙散治疗糖尿病周围神经病变(diabetic peripheral neuropathy,DPN)作用机制进行研究,为后续研究提供依据与参考。方法:在中药系统药理学数据库与分析平台(TCMSP,http://tcmspw.com/tcmsp.php)筛选四妙散的有效成分和作用靶点。在GeneCards(https://www.genecards.org)和OMIM(https://www.omim.org/)数据库筛选DPN发病相关靶基因。在R软件中计算出四妙散有效成分治疗DPN的潜在作用靶点,并构建药理作用网络。构建潜在作用靶基因蛋白互作网络(PPI),分析其基因本体功能(GO)和京都基因与基因组百科全书通路(KEGG)富集情况,筛选并对接关键活性成分与靶基因。结果:从TCMSP数据库筛选出9个苍术的有效成分,37个黄柏的有效成分,20个牛膝的有效成分,9个薏苡仁的有效成分,去重后共41个有效化学成分。筛选出DPN疾病相关靶基因1839个,发现四妙散治疗DNP共对应71个潜在作用靶蛋白。根据PPI、GO和KEGG富集结果,发现靶基因AKT1和VCAM1可能在四妙散治疗DPN的过程中发挥重要作用。对应的有效成分有4个,黄柏和牛膝共有的Coptisine(黄连碱)、苍术和牛膝共有的Wogonin(汉黄芩素)、牛膝中的28-norolean-17-en-3-ol(28-去甲齐墩果-17-en-3-ol)和Poriferasta-7,22E-dien-3beta-ol(多孔甾-7,22E-dien-3β-ol)。有效成分28-norolean-17-en-3-ol与蛋白AKT1不存在由氢键产生的连接,其余有效成分与蛋白均能通过氢键完成模拟对接。结论:四妙散各有效成分与作用靶基因间存在密切的协同关系和良好的结合活性,该方治疗DPN具有多成分、多靶点、多信号通路的特色。分子对接结果为将来实验研究奠定了基础。

Objective:To explore the potential mechanism of Simiaosan in the treatment of diabetic peripheral neuropathy(DPN)based on network pharmacology and molecular docking,and to provide evidence and reference for subsequent research.Methods:The ingredients and related targets of Simiaosan were searched from the database of TCMSP(http://tcmspw.com/tcmsp.php).The DPN-related targets were searched from GeneCards(https://www.genecards.org)and Online Mendelian Inheritance in Man Database(OMIM,https://www.omim.org/).The potential targets of the active components of Simiaosan in the treatment of DPN were calculated in R software,and the pharmacological action network was constructed.The protein-protein interaction(PPI)network was constructed,and its Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment were analyzed.The key active ingredients of Simiaosan were screened and then docked to the core target proteins.Results:9 active ingredients of Rhizoma Atractylodis,37 active ingredients of Phellodendri Chinensis Cortex,20 active ingredients of Achyranthes,and 9 active ingredients of Coix Seed were screened out,and a total of 41 active ingredients from Simiaosan were screened out after removed duplicates.A total of 1839 DPN-related target were screened out and 71 were the key targets of Simiaosan against DPN.AKT1 and VCAM1 gene were the core target on the mechanism of Simiaosan against DPN according to the analysis results of PPI,GO and KEGG.The ingredients that related to the core targets were Coptisine,Wogonin,28-norolean-17-en-3-ol and Poriferasta-7,22E-dien-3beta-ol.Molecular docking verified a well binding ability of the active ingredients to the core targets,excepted for 28-norolean-17-en-3-ol and AKT1.Conclusion:There is a close synergistic relationship and well binding activity between the active ingredients of Simiaosan and the DPN-related targets.The mechanism of Simiaosan against DPN through multi-component,multi-target and multi-signaling pathways.Molecular docking results lay a foundation for future experimental research.