Exploring The Mechanism Of Ritonavir In Combination With Itraconazole Against Candida Albicans Infection Based On Network Pharmacology And Molecular Docking Techniques

Objective:To investigate the potential mechanism of action of Ritonavir and Itraconazole combination against Candida albicans infection using network pharmacology and molecular docking techniques to provide new strategies for the discovery of new antifungal drugs.Methods:1.Screening potential action targets of Ritonavir and Itraconazole by Swiss Target Prediction,Target Net,Drug Bank,CTD databases,searching disease targets of Candida albicans infection in Gene Cards,OMIM databases,collating,removing duplicate values and obtaining intersecting targets by Venny diagram.2.The intersecting targets of Ritonavir,Itraconazole and Candida albicans infection corresponding targets were imported into STRING11.5 database for preliminary construction of protein interaction(PPI)network;the protein interaction information was imported into Cytoscape3.8.2,and the PPI network was constructed according to the node Degree value ranking of Cyto Hubba algorithm,Selection of the top five targets based on degree values.3.GO bioprocesses functional and KEGG pathway enrichment analysis of the intersectional targets of Ritonavir and Itraconazole against Candida albicans infection using the Metascape database,further exploration of Ritonavir in combination with Itraconazole against Candida albicans infection in terms of molecular function,cellular function and biological processes.4.Auto Dock and Py MOL software were used to predict the binding activity of Ritonavir and Itraconazole with the top five targets at the lowest free binding energy.Results:1.A total of 249 targets of Ritonavir,83 targets of Itraconazole,1,995 targets of Candida albicans infection and 72 intersection targets were identified.2.Through PPI network analysis,the top five targets in terms of Degree value were TNF,STAT3,IL-6,MAPK14 and CXCL8.3.GO function enrichment analysis yielded a total of 1207 entries(P < 0.01),including 86 molecular functions,49 cellular components and 1072 biological processes;KEGG pathway enrichment analysis yielded a total of 151 signaling pathways(P < 0.01).4.Ritonavir,Itraconazole and TNF,STAT3,IL-6,MAPK14 and CXCL8 were docked by molecular docking technology,and the results showed that the receptor and ligand had good binding ability.Conclusion:1.Through network pharmacology and molecular docking technology,it was found that Ritonavir and Itraconazole may play a role in anti-Candida albicans infection through multi-target and multi-pathway;2.The combination of Ritonavir and Itraconazole enhance their effects against Candida albicans infection,and they may play a synergistic role in the treatment of Candida albicans infection through the regulation of IL-6/JAK/STAT3、ERK MAPK/cFos and TNF-α/NF-κB pathways,which provides a new theoretical basis for further clarifying the mechanism of action of combination drugs against Candida albicans infection,and provides new ideas and strategies for the discovery of new antifungal drugs...