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. 2025 Jul 14:16:1578749.
doi: 10.3389/fphar.2025.1578749. eCollection 2025.

Exploring the therapeutic mechanism of itraconazole combined with ritonavir on Candida albicans infection through network pharmacology and molecular docking

Yiyang Feng  1 , Wenli Feng  1 , Jing Yang  1 , Yan Ma  1
Affiliations

Exploring the therapeutic mechanism of itraconazole combined with ritonavir on Candida albicans infection through network pharmacology and molecular docking

Yiyang Feng et al. Front Pharmacol. .

Abstract

Background: Autophagy induced by itraconazole and ritonavir was found involved in the pathogenesis of C. albicans. This study was designed to explore the possible molecular mechanism of itraconazole and ritonavir in the treatment of Candida albicans infection through autophagy pathway.

Methods: The overlapping targets of itraconazole and ritonavir, and those-related to C. albicans and autophagy were screened. Then the core targets were identified by protein-protein interaction (PPI) network analysis. Gene enrichment analysis of targets and the drug-target-pathway-disease network was constructed. The interactions between itraconazole, ritonavir and core targets were analyzed by molecular docking and molecular dynamics simulation. Finally, the core target-miRNA interaction network was constructed to predict candidate miRNAs.

Results: PPI network showed that PIK3R1, RELA, STAT3, HSP90AA1, TP53, JUN, GRB2, EGFR, ESR1 and TNF were potential core targets of autophagy therapy for C. albicans infection with itraconazole and ritonavir. Enrichment analysis showed that the two drugs may regulate the autophagy process through pathways including PI3K-AKT, IL-17, MAPK, Toll-like receptor, JAK-STAT and NF-κB. Molecular docking analysis indicated that itraconazole and ritonavir possess strong binding affinities with the cote target proteins, with binding free energies ranging from -5.6 to -9.5 kcal/mol. Key interactions were identified at the active sites of the targets, suggesting stable ligand-receptor complex formation. Itraconazole docked to PIK3R1 through SER-78 and GLU-82 (-9.3 kcal/mol), and ritonavir docked to PIK3R1 through ASN-85, GLU-1011 and arginine (ARG)-1088 (-7.7 kcal/mol). Molecular dynamics simulation of itraconazole and ritonavir with representative target genes lasted for 100 ns showed the structures of the formed complexes remained stable throughout. Finally, the candidate miRNAs including miR-486-5p, miR-411-5p.1 and miR-296-5p were identified.

Conclusion: Network pharmacological analysis showed a multi-target and multi-pathway molecular mechanism of itraconazole and ritonavir in the treatment of C. albicans infection, and provided a theoretical basis for subsequent studies.

Keywords: Candida albicans; autophagy; itraconazole; network pharmacology; ritonavir.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
The predictive target genes of itraconazole and ritonavir (A), and the Venn diagram showed the potential autophagy-related targets of itraconazole and ritonavir for treatment of Candida albicans infection (B).
FIGURE 2
FIGURE 2
A protein-protein interaction (PPI) network of the target of Candida albicans infection treated with itraconazole and ritonavir via the autophagy pathway. (A) A PPI network of top 10° targets of autophagy therapy for C. albicans infection with itraconazole and ritonavir; (B) The interaction network of top 10 targets.
FIGURE 3
FIGURE 3
The top 20 GO (Gene Ontology)-biological process (BP), CC (cellular component), and MF (molecular function) terms were (A–C) and the KEGG enrichment analysis of targets involving in the treatment of Candida albicans infection with itraconazole and ritonavir by autophagy (D).
FIGURE 4
FIGURE 4
The drug-target-pathway-disease network. The green squares represent drugs, the blue diamonds represent targets, the pink circles represent pathways, and the yellow triangles represent diseases.
FIGURE 5
FIGURE 5
Heat map of molecular docking results of itraconazole and ritonavir corresponding target protein molecules (A). The horizontal axis is the name of the drug and the vertical axis is the name of the target protein. The number in the grid represents the binding free energy (kcal/mol), the closer the color is to blue, the greater the absolute value of the binding energy, and the red part indicates that there is no correspondence between the drug and the target. Binding patterns of itraconazole and ritonavir and corresponding target proteins (B). Blue is the protein structure, green is the drug structure, orange is the binding site, yellow is the hydrogen bond, and the text is the predicted drug protein binding site and hydrogen bond length.
FIGURE 6
FIGURE 6
Molecular dynamics simulations of itraconazole and ritonavir with core target proteins. (A) RMSD analysis of 100 - ns simulation of itraconazole with HSP90AA1, PIK3R1, and ESR1; (B) RMSD analysis of 100 - ns simulation of ritonavir with RELA, HSP90AA1, and PIK3R1; (C) RMSF analysis of itraconazole with HSP90AA1, PIK3R1, and ESR1; (D) RMSF analysis of ritonavir with RELA, HSP90AA1, and PIK3R1; (E) Radius of gyration analysis of itraconazole with HSP90AA1, PIK3R1, and ESR1; (F) Radius of gyration analysis of ritonavir with RELA, HSP90AA1, and PIK3R1; (G) Solvent - accessible surface area analysis of itraconazole with HSP90AA1, PIK3R1, and ESR1; (H) Solvent - accessible surface area analysis of ritonavir with RELA, HSP90AA1, and PIK3R1.
FIGURE 7
FIGURE 7
The interaction network of core targets and miRNAs. The blue circle represents targets and the green diamond represents miRNAs.
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