IN SILICO EVALUATION OF SULFAMOYL PHENYL DERIVATIVES AS POTENTIAL DPP-4 INHIBITORS FOR THE TREATMENT OF TYPE 2 DIABETES MELLITUS: MOLECULAR DOCKING STUDIES, ADMET PROFILING, AND TOXICITY PREDICTION

Abstract

Background: Type 2 diabetes mellitus (T2DM) remains a formidable global health burden, compelling the continuous search for safer and more efficacious therapeutic agents. Dipeptidyl peptidase-4 (DPP-4) inhibitors have emerged as a clinically validated drug class owing to their glucose-dependent mechanism of incretin potentiation, conferring a low intrinsic risk of hypoglycaemia. In the present study, aimed to identify novel sulfamoyl phenyl derivatives as potential DPP-4 inhibitors through computational approaches.

Method: A structurally diverse library of 40 sulfamoyl phenyl derivatives was rationally designed and subjected to comprehensive in silico evaluation, encompassing molecular docking against the DPP-4 crystal structure (PDB ID: 2OQV), ADMET profiling via SwissADME, and multi-endpoint toxicity prediction via ProTox-3.0. Three-dimensional ligand geometries were constructed and energy-minimised using ChemDraw 3D, and docking simulations were executed with AutoDock Vina.

Results: The binding affinities across the series spanned −7.0 to −9.7 kcal/mol. The compounds, L_11 and L_33, achieved scores of −9.3 and −9.7 kcal/mol, respectively — equalling or nearly matching the reference inhibitor Sitagliptin (−9.7 kcal/mol). Both leads engaged the canonical catalytic triad residues SER630, GLU205, and GLU206, together with PHE357 and TYR662, through a combination of hydrogen bonding, hydrophobic contacts, and electrostatic interactions. ADMET analysis confirmed that the majority of compounds comply with Lipinski's rule of five, exhibit high predicted gastrointestinal absorption, and display a bioavailability score of 0.55. Toxicity profiling revealed acceptable preliminary safety windows for several derivatives, although targeted structural optimisation will be required to address hepatotoxic and nephrotoxic liabilities in a subset of analogues.

Conclusion: Sulfamoyl phenyl derivatives, particularly L_11 and L_33, demonstrated promising DPP-4 inhibitory potential with favorable binding affinity and pharmacokinetic characteristics. These findings support their further optimization and experimental validation as tractable lead scaffolds for development of next-generation DPP-4 inhibitors in diabetic management.