Identification of key genes, biological functions, and pathways of empagliflozin by network pharmacology and its significance in the treatment of type 2 diabetes mellitus.

ABSTRACT

Background: To explore the key genes, biological functions, and pathways of empagliflozin in the treatment of type 2 diabetes mellitus (T2DM) through network pharmacology. Methods: The TCMSP (a traditional Chinese medicine system pharmacology database and analysis platform) was used to screen empagliflozin's active components and targets. The target genes of T2DM were screened according to the GeneCards and OMIM databases, and a Venn diagram was constructed to obtain the target for T2DM treatment. Cytoscape 3.7.2 software was adopted to construct the drug-component-target-disease network. Functional annotation of Gene Ontology (GO) and enrichment analysis of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were performed using R software. Results: Target genes with a probability >0 were selected, among which Compound 012, Compound 060, Compound 093, Compound 111, and Compound 119 Swiss Target Prediction suggested that no similar active substances or predictable target genes were found. A "compound-target gene-disease" network was constructed, in which SLC5A2, SLC5A1, SLC5A4, SLC5A11, ADK, and ADORA2A were the core genes of T2DM. The key factors of the GO summary map included chemical reaction, membrane organelle, protein binding, and so on. The KEGG pathway summary map included the AMPK pathway, insulin resistance, the MAPK pathway, longevity-related pathway regulation, and so on. The top 10 pathways were endocrine resistance, the NF-κB signaling pathway, the HIF-1 signaling pathway, apoptosis, cell senescence, the Ras signaling pathway, the MAPK signaling pathway, the FoxO signaling pathway, the P13K-Akt signaling pathway, and the p53 signaling pathway. The binding of active compounds to key proteins was verified based on the Swiss Dock database, and the molecular docking of 193 bioactive compounds was finally verified. Among them, SLC5A2, SLC5A1, LDHA, KLK1, KLF5, and GSTP1 had better binding to the protein molecules. Conclusions: Empagliflozin may regulate the targets of SLC5A2, SLC5A1, LDHA, KLK1, KLF5, and GSTP1. There are numerous ways of treating T2DM with empagliflozin, including by regulating apoptosis, cell aging, as well as the NF-κB, HIF-1HIF-1, Ras, MAPK, FoxO, P13K-Akt, and p53 pathways.