A Network Pharmacology to Explore the Potential Targets of Canagliflozin and Dapagliflozin in Treating Atherosclerosis

Background: Atherosclerosis (AS) is an important pathological basis of many cardiovascular diseases. Canagliflozin and dapagliflozin have yielded impressive results in the treatment of cardiovascular disease in both diabetic and non-diabetic patients. In this study, we investigated their targets and mechanism involved in the treatment of atherosclerosis using network pharmacology. Methods: The potential targets of canagliflozin and dapagliflozin were gathered from the database PharmMapper. Targets associated with AS were derived from the GeneCards, Drugbank, DisGeNet, and therapeutic target databases (TTD) by searching for keywords on atherosclerosis and coronary artery disease. Overlap targets were collected by uploading drug and disease targets into jvenn. The cross-targets of the Venny plots were uploaded to the STRING database, and a protein–protein interaction (PPI) was constructed with their calculated features, aiming to reveal several key targets. Key targets were selected by using a plug-in of the Cytoscape software. Gene ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed using the database Metascape. Cytoscape was used to set up the pathways-genes network. Molecular docking with core targets and drugs was performed with AutoDock. Results: A total of 288 canagliflozin targets, 287 dapagliflozin targets and 4939 AS-related targets were obtained. A total of 191 overlapping targets were found after intersecting. Five core targets, including protein kinase B (Akt1), Mitogen-activated protein kinase 1 (MAPK1), Mitogen-activated protein kinase 14 (MAPK14), Proto-oncogene tyrosine-protein kinase SRC (SRC) and Epidermal growth factor receptor (EGFR) were collected. Pathways, biological processes, molecular functions and cellular components of canagliflozin and dapagliflozin were found. Conclusion: Canagliflozin and dapagliflozin play a role in atherosclerosis by regulating Akt1, MAPK1, MAPK14, SRC and EGFR. Our research provides further insights into the use of canagliflozin and dapagliflozin in the treatment of atherosclerosis.