Analysis of potential targets and mechanisms of Ranolazine for the treat-ment of arrhythmias caused by myocardial ischemia-reperfusion injury based on network pharmacology and computer-aided drug design meth-ods
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.
Network pharmacologyComputer-aided drug designRanolazineMyocardial ischemia-reperfusion injuryCardiac arrhythmia
万方数据
维普
