In Silico Identification of Novel Leads as Potential DPP-IV Inhibitors as Antidiabetic Agents Using Virtual Screening
Purpose: Dipeptidyl peptidase-IV (DPP-IV) is a validated therapeutic target for type 2 diabetes mellitus due to its role in incretin hormone degradation. This study aimed to identify novel small-molecule DPP-IV inhibitors from the ECBD database using an integrated virtual screening and molecular dynamics (MD) approach, acknowledging that experimental validation is necessary to confirm biological activity. Methods: Structure-based virtual screening of 5,500 ECBD compounds was performed using molecular docking to identify high-affinity ligands, followed by interaction analysis with key catalytic residues. Pharmacokinetic suitability was evaluated through in-silico ADMETox profiling. The top-ranked hits were further subjected to 100 ns MD simulations to assess complex stability and conformational effects on the DPP-IV active site. Binding free energies were calculated using the MM/GBSA method, and docking reliability was validated through redocking experiments. Results and Discussion: Five compounds EOS34295, EOS4915, EOS9480, EOS2567, and EOS62725 exhibited stronger noncovalent binding affinities than vildagliptin and formed stable interactions with essential residues, including GLU205, GLU206, ASN710, and PHE357. ADMETox predictions indicated favorable oral drug-likeness. MD simulations revealed stable protein–ligand complexes, with lower RMSD values for the hit ligands (1.20–1.51 Å) compared with vildagliptin (1.90 Å). RMSF analysis showed consistent flexibility without destabilizing fluctuations. Additional hydrogen-bond interactions with PHE357 emerged during MD simulations, indicating enhanced binding persistence. MM/GBSA analysis confirmed stronger binding energies for EOS34295 (−56.58 kcal/mol), EOS62725 (−37.90 kcal/mol), and EOS2567 (−31.27 kcal/mol) relative to vildagliptin (−23.88 kcal/mol). Conclusion: This study identifies EOS34295, EOS2567, and EOS62725 emerged as promising DPP-IV inhibitory hits with superior binding stability, supporting their potential as antidiabetic leads for future experimental validation.