Integrative molecular modelling and phytosomal encapsulation of kaempferol for pancreatic lipase inhibition in obesity therapy

ABSTRACT Introduction : The escalating prevalence of obesity necessitates safer and more effective therapeutic strategies. Traditional Chinese Medicine, through its principle of restoring metabolic homeostasis by eliminating pathological "dampness" and Qi imbalance, offers flavonoids as pharmacologically potent anti-obesity candidates. Inhibition of pancreatic lipase remains the most validated target for limiting dietary fat absorption. This study computationally evaluated TCM-relevant flavonoids against pancreatic lipase and developed an optimized phytosomal formulation of kaempferol (山柰酚) for in vitro assessment. Methods The study evaluated the pancreatic lipase inhibitory potential of selected flavonoids using molecular docking, dynamics simulations and MM-GBSA analyses and developed an optimized phytosomal formulation of kaempferol for in vitro assessment. Results Glide XP docking scores, 100-ns molecular dynamic simulations and MM-GBSA analysis demonstrated stable ligand–protein interactions, favorable binding conformations, and sustained interaction persistence throughout the simulation period. Kaempferol phytosomes were prepared using the solvent evaporation method. The optimized formulation exhibited nanoscale particle size, high zeta potential, and substantial entrapment efficiency, indicating successful complexation. Analytical characterization confirmed modification of the physicochemical state of kaempferol within the phytosomal matrix. In vitro pancreatic lipase inhibition assays demonstrated dose-dependent activity, achieving 71.79% inhibition at 200 µM with an IC₅₀ value of 131.57 μM. Conclusions These findings suggest that phytosomal delivery enhances the therapeutic potential of kaempferol, a pharmacologically revered flavonoid deeply rooted in Traditional Chinese Medicine, thereby reinforcing its promise as a TCM-derived therapeutic candidate for evidence-based obesity management.