Integrative computational, ethnomedicinal and system pharmacology approach to decipher the anti-diabetic potential of Mangifera indica L. phytochemicals
The global increase in adult Type 2 diabetes mellitus (T2DM) cases is attributed to unhealthy diets, insufficient physical activity and increased work pressure, leading to elevated glucose levels. Human dipeptidyl peptidase 4 (DPP-4) regulates post-prandial insulin release, with increased bioavailability resulting from inhibition and increased Glucagon-Like Peptide-1 (GLP-1) levels. The NAD(H)/NAD ratio affects 11-beta-hydroxysteroid dehydrogenase 1 (HSD11B1), which converts cortisone to cortisol. It promotes glucose metabolism by increasing phosphoenolpyruvate carboxykinase (PEPCK) transcription. The present study aims to identify novel lead compounds from Mangifera indica L. for T2DM therapies that could inhibit key targets DPP-4 and HSD11B1, overcoming current medication limitations. 14 phytocompounds were screened from 63 and docked against the key targets DPP-4 and HSD11B1. To evaluate the reactivity and properties of the potential molecules, a quantum-mechanical simulation was performed using an arbitrary postulate of density functional theory (DFT). The phyto-compound kaempferol exhibited higher interaction with better binding affinity against T2DM targets DPP-4 and HSD11B1 out of 14 screened phyto-constituents, followed by other compounds. Kaempferol showed optimal binding energies of -7.6 and -9.0 kcal mol-1 for DPP-4 and HSD11B1, respectively, compared with the standard drug metformin. Subsequently, kaempferol exhibited higher reactivity than the standard per quantum-chemical calculations. The molecular dynamics (MD) simulation studies of complexes with kaempferol demonstrated stable, consistent dynamics over a specific period. The results suggest that natural compounds from mango leaves may represent a promising approach for developing new therapies, potentially reducing reliance on conventional drug discovery procedures.