Exploring the bioactive properties and mechanism of Aegle marmelos in the treatment of inflammatory bowel disease through network pharmacology and a molecular docking approach.

Background: Inflammatory bowel diseases (IBD) are recurrent inflammatory conditions that occur in the gastrointestinal tract, for which current treatment does not have satisfactory results, thus we require new therapies to combat the complex pathogenesis of IBD. Herbal medicines have been used for years to cure IBD. One of the plants from Ayurveda, Aegle marmelos (AM), commonly known as Bael, which belongs to the family Rutaceae, has ethnomedicinal properties in treating IBD due to its various phytochemicals. However, the mechanisms underlying the effect of AM remain to be elucidated.

Methods: In this study, an in silico approach, molecular docking, and enrichment analysis were implemented to uncover the potential multicomponent synergistic effect and its molecular mechanism in treating IBD. Putative targets of IBD were obtained through OMIM, GeneCards, and DisGeNET databases. Compounds of AM were screened for their targets using a Swiss target prediction database and Super-PRED database. The common targets amongst AM and IBD were analyzed and the network was constructed using Cytoscape (3.10.0). Protein-protein interactions of target genes of the compounds was carried out through a STRING database. Then, the INPUT database was used to analyze the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. Molecular docking of top 6 compounds with hub targets was carried out using Autodock vina.

Results: In the study, 46 effective compounds and 358 targets of AM were identified and further analyzed, 80 hub targets depending on the degree were considered effective against IBD. Through CytoHubba we identified AKT1, SRC, MAPK3, MAPK1, EGFR, IL6, TNF, HSP90AA1 and CASP3 as the top 10 hub targets that may contribute to the mechanistic role of AM in treating IBD. Aegeline, auraptene, bergapten, imperatorin, marmesin, and nodakenin were the most potent compounds of AM and those that possess a higher binding affinity to PI3K, AKT, and EGFR. PI3-AKT signaling pathway, EGFR tyrosine kinase inhibitor, and MAP Kinase signaling pathway are the major pathways having a correlation with AM.

Conclusion: The study unveils the mechanism of AM in alleviating IBD through the EGFR-mediated PI3K/AKT pathway, stating its multi-component, multi-targeted therapeutic efficacy through multiple pathways.