2024, Vol. 28 ›› Issue (2): 208-215

Molecular docking analysis of the anti-inflammatory mechanism of Cibotium barometz and Epimedium for rheumatoid arthritis: animal experiment validation

Ran Lei1, 2, Han Haihui1, 2, Xu Bo1, 2, Wang Jianye1, 2, Shen Jun2, Xiao Lianbo2, 3, Shi Qi3   

Abstract: BACKGROUND: In clinical practice, Cibotium barometz and Epimedium have shown significant efficacy in the treatment of rheumatoid arthritis, but the complex active ingredients contained in the two have an unclear mechanism of action at the molecular level for the treatment of rheumatoid arthritis.
OBJECTIVE: Based on network pharmacology and molecular docking technology, to establish a collagen-induced arthritis model and to verify the potential targets and pathways of Cibotium barometz and Epimedium in the treatment of rheumatoid arthritis, providing reliable experimental evidence for the use of clinical formulas with Cibotium barometz and Epimedium as the main components.
METHODS: Utilizing traditional Chinese medicine research platforms, traditional Chinese medicine encyclopedias, and databases of traditional Chinese medicine and chemical components from the Shanghai Institute of Organic, effective ingredients were retrieved and identified. 3D molecular formulas were obtained from the PubChem platform and target predictions were made using PharmMapper and SwissTargetPrediction. Disease targets for rheumatoid arthritis were obtained from gene databases such as DrugBank, GeneCards, and OMIM. The intersections of targets and Cibotium barometz and Epimedium were plotted using VENNY 2.1 after calibration with the Uniport database. A protein-protein interaction network graph was constructed using the STRING platform. Gene Ontology function analysis and Kyoto Encyclopedia of Genes and Genomes enrichment analysis were performed using the Metascape platform for data visualization. A four-layered network model of traditional Chinese medicine, ingredients, targets, diseases, and pathways was constructed using Cytoscape 3.9.0. The main effective ingredients were docked with core targets using AutoDock-Vina software to explore the best binding targets. A type II collagen+adjuvant-induced arthritis rat model was established, and the effects of Cibotium barometz and Epimedium on relevant pathway targets and inflammatory cell factors were observed after 21 days of intervention.
RESULTS AND CONCLUSION: A total of 28 active ingredients from Cibotium barometz and Epimedium were selected, yielding 288 intersection targets for rheumatoid arthritis. The main ingredients included isobavachalcone, cibotium, and epimedium. The main targets included protein kinase 1 for serine/threonine (AKT1), tumor necrosis factor, and vascular endothelial growth factor A. Gene ontology analysis yielded 2 232 biological processes, mainly related to serine protein phosphorylation, positive regulation of serine/threonine protein kinase, and reactive oxygen metabolism. Kyoto Encyclopedia of Genes and Genomes enrichment analysis yielded 202 pathways, mainly involving the PI3K/AKT signaling pathway and epidermal growth factor receptor signaling pathway, which may exert therapeutic effects by regulating synovial cell apoptosis and proliferation and suppressing inflammatory factors. Molecular docking results showed the strongest binding activity and stable structure of Cibotium barometz and Epimedium with AKT1 and estrogen receptor transcription factor 1, which was closely related to apoptosis and proliferation and inflammatory signaling pathways such as PI3K/AKT. Cibotium barometz and Epimedium reduced the expression of interleukin-1β, interleukin-6, and tumor necrosis factor-α in the serum of collagen-induced arthritis rat models. Cibotium barometz and Epimedium reduced the expression of p-PI3K, p-AKT, and p-FOXO1 in the synovium of collagen-induced arthritis rat models. The results indicate that the combination of Cibotium barometz and Epimedium may exert therapeutic effects by inhibiting the proliferation of synovial cells and suppressing the expression of inflammatory factors via the PI3K/AKT/FOXO1 signaling pathway. This may be closely related to the occurrence of inflammation and bone destruction in rheumatoid arthritis, and provides a reference for the rational use and development of new drugs in clinical practice.

Key words: network pharmacology, molecular docking, Cibotium barometz, Epimedium, rheumatoid arthritis, apoptosis, proliferation, in vivo experiment, collagen-induced arthritis, animal model