The protein tyrosine phosphatase 1B (PTP1B) enzyme has been targeted in various therapeutic approaches for managing diabetes mellitus (DM). In this study, thiazolidine-2,4-dione derivatives containing a 1,3,4-thiadiazolyl moiety were selected as potential PTP1B inhibitors. In total, 41 compounds were chosen (Y1–Y41). A complete workflow of molecular docking and biomechanical experiments which included ADMET prediction, docking, 2D-QSAR modeling, and MD simulations was used to build and evaluate new PTP1B inhibitors. A predictive QSAR model was built having as its objective the design of novel compounds. Using the crystal structure of PTP1B (PDB ID: 1XBO) molecular docking was performed followed by MD simulations of 100 ns to study the stability of certain ligand–protein complex systems. With a robust QSAR model (R2=0.943 and allowed the prediction of three new compounds with good ADMET properties. Several designed molecules showed an improved inhibitory activity compared to the reference compound Y17, achieving docking scores of –9 to –10 kcal/mol. The stability of selected complexes was further evaluated by 100 ns MD simulations, followed by MM-PBSA binding free-energy calculations. Among the investigated ligands, DES3 exhibited the most favorable binding free energy (ΔG = −18.65 kcal/mol), suggesting strong and stable interactions with the PTP1B active site. These findings highlight the potential of thiazolidine-2,4-dione/1,3,4-thiadiazole hybrids as promising scaffolds for the future development of PTP1B inhibitors.
Naanaai et al. (Sun,) studied this question.