基于网络药理学和分子对接技术探讨续断促进骨折愈合的机制

doi:10.3969/j.issn.1006-7795.2022.02.019

摘要/Abstract

摘要： 目的采用网络药理学以及分子对接技术分析续断促进骨折愈合的机制。方法通过中药系统药理学数据库与分析平台(traditional Chinese medicine systems pharmacology database and analysis platform, TCMSP)检索续断有效成分,设定口服药物生物利用度(oral drug bioavailability,OB)≥30%和类药性指数(drug like index, DL)≥0.18作为筛选标准,并获得续断有效活性成分的作用基因靶点。在TTD、OMIM、GeneCards、DrugBank、PharmGkb等数据库进行搜索,获取骨折的相关基因靶点。将续断作用靶点与骨折相关基因靶点进行匹配,获取交集得到主要靶点基因。通过EVenn将结果可视化。通过DAVID、STRING数据库等对主要靶点基因进行基因本体(gene ontology,GO)、京都基因与基因组百科全书(Kyoto Encyclopedia of Genes and Genomes,KEGG)富集分析以及构建蛋白相互作用网络。通过不同算法获得主要靶点基因中的关键基因。最后通过Pymol、Autoduck等软件进行分子对接,并计算最低结合能、结合位点以及确定定活性口袋。结果通过TCMSP数据库筛选得到续断有效成分8个,作用靶点63个,删除重复靶点,最终得到作用靶点53个。通过TTD、OMIM、GeneCards、DrugBank、PharmGkb等数据库查询骨折相关作用靶点,得到5 115个相关靶点。通过匹配以及交集分析,获得续断促进骨折愈合的34个作用基因靶点。通过DAVID数据库,分析得到续断治疗骨折的作用基因靶点参与的生物学过程76个、细胞成分20个、分子功能20个。通过STRING数据库,构建续断治疗骨折的蛋白互作网络,共纳入34个基因,79个连接。平均degree参数为4.65。导入Cytoscape软件,通过计算degree以及betweenness,获取续断治疗骨折的关键基因为PTGS2、HSP90AA1、MAPK14。采用对子对接分析发现续断中生物利用度最优的有效成分(E,E)-3,5-Di-O-caffeoylquinic acid、Gentisin、Sylvestroside Ⅲ_qt与关键基因PTGS2、HSP90AA1、MAPK14最低结合能均小于0,并得到结合位点。结论通过网络药理学及分子对接技术,阐明续断促进骨折愈合的可能的潜在靶点,预测了其发挥药理作用的有效成分以及关键基因。

关键词: 续断, 骨折愈合, 网络药理学, 分子对接

Abstract: Objective To analyze the mechanism of Xuduan promoting fracture healing by network pharmacology and molecular docking technology. Methods The active components of Xuduan were acquired through traditional Chinese medicine systems pharmacology database and analysis platform (TCMSP) database by setting the oral drug bioavailability (OB)≥30% and drug like index (DL)≥0.18 as screening criteria, and the target genes of the active components were obtained. The bone fracture related genes were obtained by searching TTD, OMIM, Genecards, Drugbank and PharmGkb databases. The main target genes were obtained by matching the target genes of Xuduan active components with fracture related genes. The results were visualized by EVenn. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis of main target genes were analyzed by DAVID database and protein interaction network was constructed by STRING databases. Key genes in main target genes were obtained by degree and betweenness algorithms. Finally, Pymol and Autoduck softwares were used for molecular docking and calculating the minimum binding energy, binding site and fixed active pocket. Results Totally 8 active components and 63 target genes of Xuduan were screened by TCMSP database, and 53 target genes were obtained by deleting repeated target genes. Totally 5 115 genes related to bone fracture were obtained from TTD, OMIM, GeneCards, DrugBank and PharmGkb databases. Totally 34 main target genes were obtained by matching and intersection analysis. The 34 target genes were enriched in 76 biological processes, 20 cellular components and 20 molecular functions through DAVID database analysis. The protein interaction network was constructed by STRING database. A total of 34 genes and 79 connections were included. The average degree parameter was 4.65. Xuduan promoting bone healing key genes were PTGS2, HSP90AA1 and MAPK14 by calculating degree and betweenness in Cytoscape software. The active components with optimal bioavailability, as (E,E)-3,5-Di-O-caffeoylquinic acid, Gentisin and Sylvestroside Ⅲ_qt could bind with the key genes PTGS2, HSP90AA1 and MAPK14 at a less than 0 energy. The binding sites were obtained by Pymol and Autoduck software. Conclusion Through network pharmacology and molecular docking technology, the possible potential mechanism of Xuduan promoting fracture healing were clarified, and its effective components and key genes were predicted.

Key words: Xuduan, fracture healing, network pharmacology, molecular docking

中图分类号:

张进, 王东. 基于网络药理学和分子对接技术探讨续断促进骨折愈合的机制[J]. 首都医科大学学报, 2022, 43(2): 275-283.

Zhang Jin, Wang Dong. The study of the mechanism of Xuduan promoting fracture healing based on network pharmacology and molecular docking[J]. Journal of Capital Medical University, 2022, 43(2): 275-283.

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