Petasiphenol and Spathulenol as Promising Natural DPP-4 Inhibitors: An In Silico Multiple Ligand-Based Study Against Type 2 Diabetes Mellitus

Abstract

Type 2 Diabetes Mellitus (T2DM) is a prevalent metabolic disorder with significant global morbidity and mortality. Dipeptidyl peptidase- 4 (DPP-4) is a key enzyme regulating glucose metabolism, and its inhibition represents a promising therapeutic strategy. This study evaluated the binding affinity and interaction mechanisms of natural compounds from Impatiens balsamina and Acmella oleracea against DPP-4 (PDB ID: 2RGU) using molecular docking, with Linagliptin as a reference inhibitor. Docking results revealed that Linagliptin exhibited the strongest interactions, forming multiple hydrogen bonds, π–π interactions, and hydrophobic contacts with catalytic residues. Among the phytochemicals, Petasiphenol demonstrated the highest affinity, stabilized by hydrogen bonds and aromatic interactions, while Spathulenol showed favorable binding through a combination of polar and hydrophobic contacts. Apigenin exhibited moderate interactions, whereas sesquiterpenoids Cedrenol and Salvia-1(14)-en-1-one showed limited binding due to their predominantly hydrophobic nature. These findings indicate that natural compounds containing hydroxyl groups and aromatic scaffolds are more effective DPP-4 binders. Petasiphenol and Spathulenol emerge as promising lead compounds for further molecular dynamics, pharmacokinetic studies, and experimental validation, supporting their potential development as plant-derived antidiabetic agents.