Abstract
Despite the reported antidiabetic potential of Carpobrotus edulis, there is still a dearth of information on its modulatory role on the genes and signaling pathways implicated in Type 2 diabetes mellitus (T2DM). This study evaluated the gene-compound-pathways to lend scientific credence to the antidiabetic molecular mechanism of action of C. edulis using network pharmacology method. The results revealed that 11 metabolites of C. edulis that displayed oral drug-likeness properties presented a network of 34 common genes with T2DM. While the gene ontology analysis revealed negative regulation of apoptotic, plasma membrane, and protein kinase as the biological parameters involved, the Kyoto Encyclopedia of Genes and Genomes analysis identified endocrine resistance (ER) signaling pathway as the most significant functional parameter. The ER signaling pathway had estrogen receptors 1 and 2 (ESR1 and ESR2) as the most enriched genes implicated in T2DM relative to C. edulis. Interestingly, the top ranked C. edulis metabolites displayed higher binding affinities (ranging from -39.98 to -49.67 kcal/mol for ESR1 and -33.21 to -58.59 kcal/mol for ESR2) than the standard drugs (metformin and tamoxifen [-14.21 and -12.34 kcal/mol for ESR1 and -20.65 and -47.92 kcal/mol for ESR2, respectively]), with catechin (-49.67 kcal/mol) and epicatechin (-58.59 kcal/mol) specifically displaying the highest binding free energies for ESR1 and ESR2, respectively. The greater binding interactions, stability, and structural orientation exhibited by C. edulis metabolites further substantiated their modulatory role on the genes. Overall, the significant binding affinities, stabilities, and interactions observed with the top ranked C. edulis metabolites, especially catechin and epicatechin with the two hub genes, suggest that C. edulis possibly elicits antidiabetic activity via enhancement of cellular glucose uptake and insulin sensitivity. However, further preclinical and clinical studies on the potential of C. edulis metabolites as potential drug candidates against T2DM are encouraged.