Detailed Molecular Interaction Analysis at the DPP-4 Active Site of Aromatic Compounds from Cinnamon Bark (Cinnamomum Cassia): Binding Mechanisms and Comparison with the Gliptin Class

Abstract

This study presents a detailed residue-level interaction analysis at the active site of Dipeptidyl peptidase- 4 (DPP-4) for 13 aromatic compounds isolated from cinnamon bark (Cinnamomum cassia), integrating previously published molecular docking results with comprehensive profiling using the Protein-Ligand Interaction Profiler (PLIP). Interaction patterns — including hydrophobic contacts, hydrogen bonds, π- stacking, and salt bridges — were systematically extracted, mapped onto key active-site residues, and comparatively evaluated against six synthetic DPP-4 inhibitors of the gliptin class. The analysis demonstrates that the S1 subsite (Tyr631, Val656, Trp659, Tyr662, Tyr666, Val711) is the preferred binding locus for 12 out of 13 aromatic compounds, whereas 4-hydroxybenzaldehyde exhibits a distinctive binding mode that preferentially targets the S2 subsite and the catalytic triad. Among the natural ligands, three compounds emerged as the most promising candidates: benzyl benzoate (−7.4 kcal/mol, 9 interactions), 1-naphthalenol (−6.352 kcal/mol, 11 interactions), and 1-phenyl-1,2- propanedione (−6.086 kcal/mol, 6 interactions), with 1-naphthalenol displaying a multi-point interaction profile that simultaneously engages S1, S2, and catalytic residues via a combination of hydrophobic contacts and hydrogen bonds. Comparative profiling with the gliptins reveals that the aromatic compounds excel in hydrophobic contacts within S1 but generally lack interactions with S2 and the catalytic triad — a key distinction that largely accounts for their lower binding affinity and selectivity. Structure-activity relationship (SAR) analysis suggests that combining aromatic hydrophobic scaffolds with appropriately oriented hydrogen-bond donors/acceptors directed toward S2 and the catalytic triad constitutes a rational strategy for optimizing natural-origin DPP-4 inhibitors. Collectively, these findings provide a robust mechanistic framework for the design and development of cinnamon-derived DPP-4 inhibitor candidates as potential therapeutics for type 2 diabetes mellitus