基于网络药理学和分子对接探讨补骨脂-肉豆蔻药对治疗肠易激综合征的机制研究

Investigating the action mechanism of psoralea fructus-nutmeg on irritable bowel syndrome based on network pharmacology and molecular docking

目的:补骨脂-肉豆蔻(Psoralea Fructus-Nutmeg,PN)是一组常用中药配伍,在中国已被用于治疗肠易激综合征(Irritable Bowel Syndrome,IBS),本研究旨在探讨PN治疗IBS的潜在机制。方法:通过查阅文献获得PN药对的入血活性成分,上传到Pharm mapper获得潜在目标靶点。采用Cytoscape 3.8.0软件构建化合物-靶点网络。通过DisGeNET、CTD、TTD数据库查找IBS相关基因,利用Cytoscape 3.8.0绘制疾病基因蛋白质-蛋白质相互作用网络。利用DAVID数据库进行了基因本体论(GO)功能富集分析和京都基因与基因组百科全书(KEGG)通路富集分析。最后,利用AutoDockVina进行了分子对接验证。结果:得到29个药物的活性成分和673个预测的靶基因,得到IBS靶点926个,其中91个与IBS靶点重叠,被认为是潜在的治疗靶点。分析表明,PN的主要靶点丝裂原活化蛋白激酶(Mitogen-activated Protein Kinase,MAPK)1、乙型肝炎、丝氨酸/苏氨酸蛋白激酶(Threonine-protein Kinase,AKT)1等通过参与FoxO信号通路、肿瘤坏死因子(Tumor Necrosis Factor,TNF)信号通路、磷脂酰肌醇-3-激酶(Phosphatidylinositol 3-kinase,PI3K)-AKT信号通路等关键通路的反应,改善胃肠黏膜代谢,具有抗炎、抗凋亡、抗氧化和自噬作用,从而缓解了IBS的进展。分子对接结果表明,补骨脂双氢黄酮甲醚、补骨脂异黄酮、小茴香醇A、小茴香醇C、芳香素A2、芳香素B1、芳香素C1、芳香素D1、芳香醇A、补骨脂苷与AKT1、MAPK1、维甲酸受体RXRα(Retinoic Acid Receptor RXR-alpha,RXRA)、雌激素受体1(Estrogen Receptor 1,ESR1)、糖皮质激素受体(Glucocorticoid Receptor,NR3C1)、MAPK14、热休克蛋白HSP 90-α(Heat Shock Protein HSP 90-alpha,HSP90AA1)、MAPK8、过氧化物酶体增殖物激活受体α(Peroxisome Proliferator-activated Receptor alpha,PPARA)、胰岛素样生长因子Ⅰ(Insulin-like Growth Factor I,IGF1)、一氧化氮合酶(Nitric Oxide Synthase,NOS)2、芳香左旋氨基酸脱羧酶(Aromatic-L-amino-acid Decarboxylase,DDC)具有良好的结合活性。结论:本研究表明,PN可以通过多组分、多目标和多通道联合作用参与IBS的治疗。

Objective:Psoralea fructus-nutmeg,a group of commonly used compatible TCM medicines,has been used to treat irritable bowel syndrome in China.In this study,the underlying mechanism of PN on IBS was investigated mainly.Methods:The bloodentering active ingredients of PN medicine pair were obtained by retrieving the literature,and uploaded to Pharm mapper to obtain potential targets.The compounds-targets network was constructed by Cytoscape 3.8.0 software.IBS-related genes were searched in DisGeNet,CTD,and TTD databases.PPI network of disease-gene was drew by Cytoscape 3.8.0 software.The GO enrichment analysis and KEGG pathway enrichment analysis were performed by DAVID database.Finally,molecular docking validation was performed by AutoDockVina software.Results:29 active ingredients and 673 predicted target genes were obtained,with 926 IBS targets,of which 91 overlapped with IBS targets and were considered as potential acting targets.The analysis showed that the main targets of PN,such as MAPK1,Hepatitis B,AKT1,etc.,have anti-inflammatory,anti-apoptotic,anti-oxidative and autophagic effects by participating in key pathways such as FoxO signaling pathway,TNF signaling pathway,and PI3K-AKT signaling pathway.They can improve gastrointestinal mucosal metabolism,thereby alleviating the progression of IBS.The molecular docking results showed that bavachinin,corylin,fragnasol A,fragnasol C,fragransin A2,fragransin B1,fragransin C1,fragransin D1,fragransol A,and psoralenoside had good binding activity with AKT1,RXRA,MAPK1,ESR1,NR3C1,MAPK14,HSP90AA1,MAPK8,PPARA,IGF1,NOS2,and DDC.Conclusion:This study showed that PN can be involved in the treatment of IBS by the combined action of multi-component,multi-target and multi-channel.