Cinnamic acid and its derivatives on dipeptidyl peptidase 4: Structure-activity relationship and mechanism of inhibition

Abstract

Dipeptidyl peptidase 4 (DPP4), which breaks down glucagon-like peptide 1 (GLP-1), is closely associated with glucose metabolism, and the inhibition of this enzyme is one of the important targets for the treatment of diabetes. Traditionally cinnamon and bitter melon have been in wide use in diabetes treatment, and cinnamic acid (CIA) as its main ingredient is expected to be an ideal DPP4 inhibitor. In vitro inhibition experiments showed that CIA had the lowest IC₅₀ (33.56 ± 1.13 mM) compared to the other substances in the study, suggesting that it was more effective in inhibiting DPP4. Analyses showed that adding hydroxyl and methyl groups to CIA's aromatic ring reduced its effect on DPP4; CIA and its derivatives were inhibited in a mixed way. With the exception of ferulic acid (FA), CIA and its derivatives quenched the fluorescence of DPP4 via a static quenching mechanism. Thermodynamic parameters show that the binding of CIA (the most inhibitory compound) to DPP4 was spontaneous and driven by hydrogen bonding. Atomic force microscopy and circular dichroism spectroscopy analyses reveal that upon binding with DPP4, CIA underwent a conformational change. Molecular docking results highlight, while introducing hydroxyl and methoxy groups on the aromatic ring, the superior binding capacity of CIA diminished. The study confirms that CIA is an ideal inhibitor with the highest absolute value of binding energy (−5.8) and the lowest IC₅₀ compared to other substances. By clarifying the inhibition mechanism of DPP4,the study thus provides dietary guidance for diabetic patients.