Ligand-based design of potent Dipeptidyl Peptidase-IV (DPP-IV) inhibitors in heterocyclic compounds using QSAR, docking, ADMET, and pharmacological profiling for anti-diabetic potential.

ABSTRACT Type 2 Diabetes Mellitus (T2DM) is characterized by high glucose levels in the blood and impaired insulin function, often leading to complications like visual impairment, amputation, and nephropathy. It is a global health challenge and is projected to become the seventh leading cause of mortality. This research aimed to design effective and safer Dipeptidyl Peptidase-IV (DPP-IV) inhibitors as potential T2DM treatments. Five QSAR models were developed, the third model was the most robust, with R² = 0.9904, Q²cv = 0.9836, and R²pred = 0.8989. Based on this model, the newly designed compounds, yielding pIC50 values range 8.1015–8.2760, better than the template (pIC50=8.0), and the reference drug Sitagliptin (pIC50). Docking studies revealed better binding affinities for the newly designed compounds. These compounds exhibited non-harmful profiles and good pharmacokinetics. Using Material Studio v8.0, a Quantitative structure-activity relationship (QSAR) model was constructed and validated through both internal and external assessment procedures. Virtual screening identified a template compound that underwent structural modifications to enhance efficacy. Molecular docking studies using Protein Data Bank data (PDB ID: 3c59) pinpointed active site residues. The pharmacological characteristics of the compounds were evaluated using ADMETlab, SwissADME, and pKCSM. The findings suggest the designed DDP-IV inhibitors are potential candidates for T2DM treatment, giving better results and safety compared to the template and reference drug (Sitagliptin) used in this study. Keywords QSAR, Type 2 Diabetes Mellitus (T2DM), Ligand-based design, Heterocyclic derivatives, Dipeptidyl Peptidase-IV (DPP-IV) inhibitors, Molecular docking, ADMET, and Pharmacokinetic profiling