Virtual screening and safety assessment identify repurposable DPP-4 inhibitors from FDA approved drugs

Type 2 diabetes mellitus (T2DM) remains a major global health challenge, and although dipeptidyl peptidase-4 (DPP-4) inhibitors are effective therapeutic agents, their widespread use is limited by concerns regarding cost and adverse effects. Drug repurposing offers an efficient strategy for identifying new therapeutic applications for FDA-approved drugs with established safety profiles. However, previous computational studies have primarily focused on binding affinity and have rarely integrated systematic clinical safety assessment into the candidate selection process. In this study, we performed high-throughput molecular docking of 1,500 FDA-approved drugs against DPP-4 to identify promising repurposing candidates for T2DM. Compounds with binding energies below − 8.0 kcal/mol were further evaluated through comprehensive safety screening using FDA prescribing information and established medical databases. The docking protocol was internally validated by successfully identifying approved DPP-4 inhibitors among the top-ranked compounds. Ligand efficiency was used as a size-normalized metric to complement binding affinity comparisons, ensuring that compound prioritization accounted for molecular size differences. Among the screened drugs, Telmisartan demonstrated strong binding affinity (ΔG = − 11.0 kcal/mol) with favorable ligand efficiency (LE = 0.285), comparable to the approved DPP-4 inhibitor Sitagliptin (ΔG = − 9.8 kcal/mol, LE = 0.350). Although Icatibant exhibited the strongest binding among clinically acceptable compounds (ΔG = − 12.5 kcal/mol), its lower ligand efficiency (LE = 0.136) reflects its peptidic nature and larger molecular size, distinguishing it from more drug-like small-molecule candidates. Bivalirudin, Digoxin, and Irbesartan also showed favorable interactions with the DPP-4 active site. The integration of molecular docking with systematic clinical safety evaluation and ligand efficiency analysis enabled prioritization of compounds with both favorable binding characteristics and acceptable safety profiles. These findings identify Telmisartan and Icatibant as promising candidates for experimental validation and demonstrate that combining computational screening with clinical safety assessment provides a robust framework for accelerating drug repurposing for T2DM.