摘要
目的通过构建仙灵骨葆成分与靶点网络和蛋白相互作用网络,从而进行富集分析确定涉及的生物过程和通路,研究复方仙灵骨葆治疗骨质疏松(osteoporosis,OP)的潜在作用机制。方法通过检索TCMSP数据库筛选出仙灵骨葆的活性成分,并预测其靶点,并与TTD数据库、Genecards数据库、OMIM数据库以及PharmGKB数据库获得的OP相关靶点取交集,进而得到仙灵骨葆治疗OP的潜在靶点。将对比结果处理后输入Cytoscape软件中构建"仙灵骨葆-化合物-骨质疏松靶点"网络,利用String数据库和Cytoscape构建蛋白相互作用网。后利用Bioconductor数据库进行GO生物功能和KEGG通路富集分析。最后对关键化合物及靶点进行分子对接。结果分析结果得到仙灵骨葆89个活性成分,预测靶点1525个,3938个已知的OP发病相关的靶点基因。取疾病基因与药物靶点的交集得到153个基因靶点,经蛋白相互作用网络及拓扑分析后得到36个核心靶点,125个相互作用关系。富集分析显示主要通路集中在成骨破骨相关通路、免疫炎症通路,也有癌症、病毒感染等其他通路富集其中。进一步筛选核心靶点及化合物进行分子对接结果显示STAT3、MPAPK14、JUN、IL2以及EGFR作为核心靶点蛋白可与Cryptotanshinone(隐丹参酮)、Chryseriol(金圣草黄素)、Anhydroicaritin(淫羊藿苷元)、Quercetin(五羟黄酮)以及Luteolin(木犀草素)等小分子稳定结合。结论该研究通过网络药理学及分子对接的方法,找到了仙灵骨葆中的可能活性成分以及骨质疏松疾病潜在靶点并预测了仙灵骨葆影响骨质疏松的关键通路:促进成骨细胞的增殖并且抑制破骨细胞的相关通路从而达到骨量的增加,此外,还作用于免疫及血管生成相关通路改善骨的微环境,从而达到治疗骨质疏松的目的。为说明仙灵骨葆治疗骨质疏松的作用机制提供了理论依据,为进一步研究相关药物治疗骨质疏松的分子作用机制、新药开发、疾病的治疗等提供了新的思路和方法。
Objective By constructing Xianling Gubao Decoction (仙灵骨葆) components and target network and protein-protein interaction network to carry out enrichment analysis to determine the biological processes and pathways involved,we reveal the potential mechanism of Xianling Gubao Decoction for the treatment of osteoporosis(OP). Methods Through analyse the active ingredients of Xianling Gubao Decoction by searching the TCMSP database and predict their targets,and then intersect with the OPrelated targets obtained from the TTD database,Genecards database,OMIM database and PharmGKB database to obtain Xianling Gubao Decoction potential target for treating OP. The comparison results are then input into Cytoscape to construct the"Xianling Gubao Decoction-compound-osteoporosis target"network,and the protein interaction network is constructed using the String database and Cytoscape. Subsequently,use the Bioconductor database to analyze the enrichment of GO biological functions and KEGG pathway. Finally,the key compounds and targets are screened out by the method of molecularly docked. Results The analysis results obtained 89 active ingredients of Xianling Gubao Decoction,with 1525 predicted targets and 3938 known target genes related to the pathogenesis of OP. Taking the intersection of disease genes and drug targets,153 gene targets were obtained. After analysing protein interaction network and topology analysis,36 core targets and 125 interaction relationships are obtained. Enrichment analysis showed that the main pathways are concentrated in osteoblastic and osteoclast-related pathways,immuno-inflammatory pathways,and other pathways such as cancer and viral infection were also enriched. Further analysing of core targets and compounds for molecular docking results showed that STAT3,MPAPK14,JUN,IL2 and EGFR as core target proteins can be combined with cryptotanshinone,chryseriol,anhydroicaritin,quercetin,luteolin and other small molecules which form stable binding. Conclusion This study found several possible active ingredients in Xianling Gubao Decoction and potential targets of osteoporosis through network pharmacology and molecular docking methods. By analysing the result,we predict the key pathways of Xianling Gubao Decoction affecting osteoporosis:promotion osteoblasts proliferate and inhibit osteoclast related pathways to increase bone mass. In addition,they also act on immune and angiogenesis-related pathways to improve the bone microenvironment,contributing to the purpose of treating osteoporosis. It provides a theoretical basis for explaining the mechanism of Xianling Gubao Decoction treatment of osteoporosis,and provides new ideas and methods for further research on the molecular mechanism of action of related drugs in the treatment of osteoporosis,new drug development,and disease treatment.
作者
关健雷
王秋园
刘沛
习文青
张启栋
郭万首
GUAN Jianlei;WANG Qiuyuan;LIU Pei;XI Wenqing;ZHANG Qidong;GUO Wanshou(Beijing University of Chinese Medicine,Beijing 100029,China;China-Japan Friendship Hospital,Beijing 100029,China)
出处
《辽宁中医药大学学报》
CAS
2021年第2期57-65,共9页
Journal of Liaoning University of Traditional Chinese Medicine
基金
国家自然科学基金(81673776,81703896)。
关键词
仙灵骨葆
骨质疏松
网络药理学
分子对接
Xianling Gubao Decoction(仙灵骨葆)
osteoporosis
network pharmacology
molecular docking
