Exploring the mechanism of Radix Bupleuri in the treatment of depression combined with SARS-CoV-2 infection through bioinformatics, network pharmacology, molecular docking, and molecular dynamic simulation.

Background: Radix Bupleuri is commonly used in treating depression and acute respiratory diseases such as SARS-CoV-2 infection in China. However, its underlying mechanism in treating major depressive disorder combined with SARS-CoV-2 infection remains unclear.

Aim: This study aims to elucidate the pharmacological mechanisms of Radix Bupleuri in treating major depressive disorder combined with SARS-CoV-2 infection, employing bioinformatics, network pharmacology, molecular docking, and dynamic simulation techniques.

Method: Active ingredients and drug target genes of Radix Bupleuri were collected from TCMSP, PubChem, SwissTargetPrediction, and SuperPred databases. Differentially expressed genes were analyzed using datasets of SARS-CoV-2 infection and major depression disorder from the GEO database. The key genes were identified by using GO and KEGG functional analyses and STRING database. Machine learning methods were employed to predict core target gene, and ROC curve analysis validated the models' accuracy and the core gene expression had been analyzed and validated with other datasets. Molecular docking and dynamic simulation were conducted to verify the affinity of the active ingredients with core target gene. Finally, immune infiltration and correlation analyses between core target genes and immune cells were performed.

Results: A total of 15 active ingredients, 1898 differentially expressed genes related to SARS-CoV-2 infection, and 814 differentially expressed genes related to major depression disorder were collected. 18 common genes were identified at the intersection of Radix Bupleuri, major depression disorder, and SARS-CoV-2 infection. The key gene JAK2 was identified through PPI network construction and machine learning model predictions. Molecular docking showed that the binding energies of the active ingredients with JAK2 were all below - 5 kcal/mol, with petunidin exhibiting the highest affinity. Molecular dynamic simulations further suggested stable interactions with JAK2. Immune infiltration analysis suggested that Radix Bupleuri in the context of depression combined with SARS-CoV-2 infection may promote the activation and generation of B cells, CD4 T cells, and CD8 T cells, while inhibiting the activation of mature dendritic cells, macrophages, natural killer cells, and neutrophils. Correlation analysis of JAK2 with immune cells indicated an association with macrophage activation and the inhibition of memory B cells and activated B cells.

Conclusion: The active ingredients of Radix Bupleuri may exhibit both antidepressant and antiviral pharmacological effects in the progression of major depression disorder combined with SARS-CoV-2 infection, through a mechanism closely associated with the JAK2 target.