Structure‐Based De Novo Design of Novel Dual DPP IV and PTP 1B Inhibitors (DDPI's)

ABSTRACT

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.