基于网络药理学和分子对接探讨苓桂术甘汤治疗冠心病的作用机制

Mechanism investigation of Linggui Zhugan Decoction in the treatment of coronary heart disease based on network pharmacology and molecular docking

苓桂术甘汤是出自伤寒论的经典名方,临床上对治疗冠心病(coronary heart disease,CHD)具有显著疗效。由于苓桂术甘汤复杂的分子组成和多样的药学活性,且关于其治疗CHD的基础理论研究较少,目前苓桂术甘汤治疗CHD的作用机制和靶点尚未完全阐明。本文采用网络药理学的研究方法探索苓桂术甘汤治疗CHD的作用机制,并利用分子对接验证药物效应分子与靶点间的相互作用。本文通过TCMSP数据库获取苓桂术甘汤中103个有相关靶点信息的活性成分及对应靶点,通过GeneCards数据库和DisGeNET数据库获取4618个CHD相关靶点蛋白。将苓桂术甘汤与CHD的交集靶点导入到Cytoscape3.9.1软件中构建“苓桂术甘汤-活性成分-CHD作用靶点”网络,并利用STRING数据库获取交集靶点相互作用关系,筛选出AKT1、TP53、STAT3等核心靶点并绘制PPI网络。利用交集靶点在David数据库中进行GO和KEGG富集分析发现,苓桂术甘汤通过调控细胞凋亡、细胞增殖、血管生成、胆固醇代谢、炎症反应以及对脂多糖、缺氧、肿瘤坏死因子的响应等生物学过程和AGE-RAGE、脂质与动脉粥样硬化、流体剪切应力与动脉粥样硬化等信号通路发挥治疗作用。利用AutoDock软件进行分子对接,本文验证了关键活性成分与核心靶点具有较好的结合活性。综上,苓桂术甘汤可能是通过槲皮素、山奈酚、柚皮素、异鼠李素、芒柄花黄素作用于AKT1、TP53、STAT3、IL-6、EGFR等核心靶点进而调控AGE-RAGE、脂质与动脉粥样硬化、流体剪切应力与动脉粥样硬化等多条信号通路发挥治疗CHD的作用。

Linggui Zhugan Decoction is a classic prescription that has been clinically demonstrated to be effective for the treatment of coronary heart disease(CHD).However,the precise mechanism of action through which it exerts its therapeutic effect is still not fully understood due to its complex molecular components and diverse pharmacological activities.Thus,we aimed to utilize the network pharmacology approach to understand the mechanism of action of Linggui Zhugan Decoction in treating coronary heart disease,and perform molecular docking for initial verification.The 103 active ingredients of Linggui Zhugan Decoction were obtained through the TCMSP database,while 4618 CHD-related targets were sourced from GeneCards and DisGeNET databases.The intersection targets of Linggui Zhugan Decoction and CHD were imported into the Cytoscape3.9.1 software in order to construct a network of the"Linggui Zhugan Decoction-active ingredients-CHD targets".By using the STRING database,the interactions between the intersection targets were identified,leading to the selection of core targets such as AKT1,TP53,STAT3,etc.,as well as the drawing of the PPI network.GO and KEGG enrichment analysis were carried out utilizing intersection targets from the David database,which indicated that Linggui Zhugan Decoction was involved in multiple biological processes,comprising of cell apoptosis,cell proliferation,angiogenesis,cholesterol metabolism,inflammatory response,response to lipopolysaccharide,hypoxia and tumor necrosis factor,as well as signaling pathways such as AGE-RAGE,Lipid and atherosclerosis,Fluid shear stress and atherosclerosis.The binding between the main active ingredients and main targets was predicted to be strong through molecular docking.Linggui Zhugan Decoction has been shown to be therapeutically effective for coronary heart disease,due to its list of components:quercetin,kaempferol,naringenin,isorhamnetin,and formononetin,all of which target proteins such as AKT1,TP53,STAT3,IL-6,EGFR et al.,affecting the AGE-RAG,lipid and atherosclerosis,fluid shear stress and atherosclerosis,and other signaling pathways.