基于网络药理学及计算机辅助药物设计方法分析雷诺嗪治疗心肌缺血再灌注损伤致心律失常的潜在靶点及机制

Analysis of potential targets and mechanisms of Ranolazine for the treatment of arrhythmias caused by myocardial ischemia-reperfusion injury based on network pharmacology and computer-aided drug design methods

目的利用网络药理学方法和计算机辅助药物设计策略,分析雷诺嗪对心肌缺血再灌注损伤(MIRI)致心律失常的潜在治疗靶点及机制。方法采用Swiss Target Prediction数据库和DrugBank数据库预测雷诺嗪潜在的作用靶点。采用GeneCards数据库搜集MIRI和心律失常疾病的靶点,检索时间为建库至2023年1月26日,将雷诺嗪、MIRI和心律失常相关靶点进行交集比对以获取雷诺嗪治疗MIRI致心律失常的关键靶点。利用STRING数据库和Cytoscape软件绘制靶点蛋白互相作用网络。利用DAVID数据库对靶点进行信号通路富集分析。利用Cy-toscape软件构建药物-靶点-信号通路网络。利用分子对接软件验证雷诺嗪与交集靶点结合能力。最后通过分子相似性分析及分子动力学模拟研究,验证预测靶点的准确性。结果筛选获得雷诺嗪治疗MIRI致心律失常的潜在作用靶点30个。通过蛋白互相作用分析共获得8个核心靶点,包括SRC、PIK3CA、MAPK8、MAPK14、JAK1、MAP2K1、JAK2和PIK3CG。GO生物分析共筛选出177个生物学过程,其中包括123个细胞生物过程,23个细胞组成和31个分子功能。KEGG分析发现119条相关信号通路。分子对接分析结果显示,雷诺嗪与8个核心靶蛋白均具有较好的亲和力。分子相似性分析结果显示,雷诺嗪与8个核心靶蛋白原配体都存在一定相似性。分子动力学模拟了相关性最高的3个靶点(SCR、PIK3CA和MAPK8),结果显示雷诺嗪表现出MAPK8和SCR抑制剂潜力,而对PIK3CA的抑制剂位点结合潜力相对较差,结合文献复习,推测出雷诺嗪对MIRI致心律失常治疗作用的最相关分子机制。结论雷诺嗪可通过多靶点、多途径治疗MIRI致心律失常,这对促进治疗MIRI致心律失常靶向药物的研发及临床应用具有重要意义。

Objective The potential therapeutic targets and mechanisms of Ranolazine for arrhythmias induced by myocar-dial ischemia-reperfusion injury(MIRI)were analyzed using network pharmacology and computer-aided drug design strategies.Methods Swiss Target Prediction database and DrugBank database were used to predict the potential targets of action of Ranolazine.GeneCards database was used to collect targets for MIRI and arrhythmogenic diseases,retrieved on January 26,2023,and intersection of Ranolazine,MIRI and arrhythmia-related targets were compared to obtain key targets for Ranolazine for MIRI-induced arrhythmias.The target protein interaction network was mapped using the STRING database and Cytoscape software.The DAVID database was used to enrich the targets for signaling pathway analysis.Construct drug-target-signaling pathway network using Cytoscape software.Molecular docking software was used to verify the binding ability of Ranolazine to the intersecting targets.Finally,the accuracy of the predicted targets was verified by molecular similarity analysis and molecular dynamics sim-ulation studies.Results Thirty potential targets of Ra-nolazine for MIRI induced arrhythmia were screened.A total of 8 core targets were identified by protein interaction analysis,including SRC,PIK3CA,MAPK8,MAPK14,JAK1,MAP2K1,JAK2 and PIK3CG.177 biological processes were screened by GO bioanalysis,including 123 cellular biological processes,23 cellular components and 31 molecular functions.119 relevant signaling pathways.Molecular docking analysis showed that Ranolazine had good affinity with all 8 core target proteins.Molecular similarity analysis showed that Ranolazine had some similarity with all eight core target protein proligands.Molecular dynamics simulations of the three most relevant targets(SCR,PIK3CA and MAPK8)showed that Ranolazine exhibited MAPK8 and SCR inhibitor potential,while the inhibitor site binding potential for PIK3CA was relatively poor.Combined with literature review,the most relevant molecular mechanism for the therapeutic effect of Ranolazine on MIRI-induced arrhythmias was postulated.Conclusion Ranolazine can treat MIRI-causing arrhythmias through multiple targets and multiple pathways,which is important to promote the development and clinical application of targeted drugs for the treatment of MIRI-causing arrhythmias.