Singh_2026_Chem.Biodivers_23_e02643

Inhibition of DPP IV and PTP 1B constitutes a legitimate approach in modulating glucose homeostasis, thereby representing a viable therapeutic strategy for managing T2DM. This study employed a novel structure-based de novo design approach for developing dual DPP IV and PTP 1B inhibitors (DDPI's) with synergistic anti-hyperglycemic potential to effectively manage T2DM. By leveraging high-resolution protein structures, a specialized ligand library was designed employing a de novo approach to perform virtual screening. Molecular docking studies revealed four promising lead candidates, that is, YS-3, YS-5, YS-14, and YS-15 (>-138.26 kcal/mol in DPP IV while >-150.29 kcal/mol in PTP1B), with higher binding affinities as compared to clinical standard inhibitors, Vildagliptin (-103.46 kcal/mol; DPP IV) and Ertiprotafib (-141.91 kcal/mol; PTP 1B). Further, molecular dynamics (MD) and MM-GBSA analyses were performed to comprehend the thermodynamic stability of these leads. Analysis of 100 ns trajectories, integrating depth-based PCA, FEL, and DSSP, enabled identification of key intermolecular contacts responsible for the dual inhibitory behavior. DFT-based electronic profiling and ADMET predictions confirmed the biological viability and drug-like properties. These findings provide a robust structural blueprint for DDPI's with improved affinity, along with a better understanding of the inhibitory mechanisms.