Computational discovery of fenugreek-paitan-turmeric (FPT) bioactive compounds targeting SGLT2 and DPP-4 for glucose homeostasis regulation.

Objectives: This study aimed to evaluate the bioactive compounds identified in fenugreek-paitan-turmeric (FPT) by liquid chromatography-high resolution mass spectrometry analysis and their interactions with dipeptidyl peptidase-4 (DPP-4) and sodium-glucose cotransporter-2 (SGLT2), which are associated with glucose regulation. Methods: Computational analyses were conducted, including molecular docking to screen potential compounds and molecular dynamics simulations, where 250 ns trajectories were evaluated to assess complex stability, and further validated using molecular mechanics Poisson-Boltzmann surface area (MM/PBSA), dynamic cross-correlation matrix (DCCM), and principal component analysis (PCA). Results: Molecular docking identified (+)-ar-turmerone and β-carboline-3-carboxylic acid as compounds with moderate binding affinities toward DPP-4 (-6.9 kcal/mol) and SGLT2 (-8.6 kcal/mol), respectively. Molecular dynamics simulations indicated a more favorable interaction with SGLT2 than DPP-4, although structural fluctuations were observed, particularly after 100 ns. MM/PBSA analysis identified a favorable binding free energy for SGLT2 of -42.135 kJ/mol, whereas DPP-4 had a positive value of +53.907 kJ/mol, suggesting unfavorable binding. These findings were supported by DCCM analyses and PCA, which indicated more constrained motions in the SGLT2 complex relative to DPP-4. Conclusions: In this study, preliminary computational insights were obtained into the interactions of FPT-derived compounds with SGLT2 and DPP-4. The results suggested a more favorable interaction with SGLT2, whereas the binding to DPP-4 appeared less stable. Further experimental validations, including in vitro and in vivo studies, are needed to validate their efficacy in the management and pathogenesis of diabetes.