Enzymatic Fructosylation of Phenolic Compounds: A New Alternative for the Development of Antidiabetic Drugs

Enzymatic fructosylation has emerged as a strategy to enhance the hydrophilicity of polyphenols by introducing sugar moieties, leading to the development of phenolic glycosides, which exhibit improved solubility, stability, and biological activities compared to their non-glycosylated forms. This study provides a detailed analysis of the interactions between five phenolic fructosides (4MFPh, MFF, DFPh, MFPh, and MFPu) and twelve proteins (11β-HS1, CRP, DPPIV, IRS, PPAR-γ, GK, AMPK, IR, GFAT, IL-1ß, IL-6, and TNF-α) associated with the pathogenesis of T2DM. The strongest interactions were observed for phlorizin fructosides (DFPh) with IR (−16.8 kcal/mol) and GFAT (−16.9 kcal/mol). MFPh with 11β-HS1 (−13.99 kcal/mol) and GFAT (−12.55 kcal/mol). 4MFPh with GFAT (−11.79 kcal/mol) and IR (−12.11 kcal/mol). MFF with AMPK (−9.10 kcal/mol) and PPAR- γ (−9.71 kcal/mol), followed by puerarin and ferulic acid monofructosides. The fructoside group showed lower free energy binding values than the controls, metformin and sitagliptin. Hydrogen bonding (HB) was identified as the primary interaction mechanism, with specific polar amino acids such as serin, glutamine, glutamic acid, threonine, aspartic acid, and lysine identified as key contributors. ADMET results indicated favorable absorption and distribution characteristics of the fructosides. These findings provide valuable information for further exploration of phenolic fructosides as potential therapeutic agents for T2DM.