In silico approaches to identify novel anti-diabetic type 2 agents against dipeptidyl peptidase IV from isoxazole derivatives of usnic acid.

Diabetes mellitus (DM) is a serious worldwide health issue in the twenty-first century. Additionally, DM, a metabolic endocrine illness that affects the digestion of proteins, carbohydrates, and lipids, has a death rate of 4.9 million individuals globally. This study aims to find anti-diabetic inhibitor for type 2 diabetes (T2D) that inhibits the dipeptidyl peptidase IV (DPP-IV) enzyme using in silico methods. From a range of published literature sources, thirty (30) isoxazole derivatives of UA (IDUA) were selected for this study. To ascertain the possible inhibitory effects of IDUA, ADMET, molecular docking, density functional theory analyses, molecular dynamic simulation and MM/PBSA were conducted. Eleven compounds (1, 2, 3, 4, 7, 13, 18, 21, 22, 24, and 27) were selected from the ADMET study, which were subjected to perform molecular docking against the DPP-IV enzyme of T2D, and findings indicated two compounds (compound 2 and compound 3) showed comparable binding affinity with the reference compound "Linagliptin". In contrast to the reference molecule, which had a binding affinity of - 8.6 kcal/mol against DPP-IV, compound 2 and compound 3 have binding affinities of - 8.1 and - 8.0 kcal/mol, respectively. Furthermore, based on Lipinski's Rule of Five, E_LUMO, E_HOMO, band energy gap, drug-likeness and DFT-based studies demonstrated druggability and high reactivity for these compounds. In addition, the molecular dynamic (MD) techniques to confirm that docked complexes remained stable and that the binding orientation obtained during docking tests were accurate. These compounds may be investigated in vitro and in vivo for the development of potential DPP-IV of T2D inhibitors.

Supplementary information: The online version contains supplementary material available at 10.1007/s13205-025-04287-5.