One health in action: Structure-based drug repurposing for porcine delta and epidemic diarrhea viruses

• A validated One Health computational workflow identified antiviral candidates targeting PEDV and PDCoV 3CLpro. • Re -docking of GC376 (RMSD = 1.84 Å) confirmed the reliability of the molecular docking protocol. • Saquinavir demonstrated the most stable binding through docking, conserved residue interactions, and 100-ns MD simulations. • ADME/Tox profiling supported saquinavir’s translational potential. Porcine Delta Coronavirus (PDCoV) and Porcine Epidemic Diarrhea Virus (PEDV) remain major enteric pathogens of swine, responsible for severe diarrheal disease and high mortality among neonatal piglets. Despite intensive control measures, there are currently no approved antiviral treatments. This study applies a One Health -oriented, structure-based drug repurposing approach to identify potential inhibitors of the viral 3C-like proteases (3CLpro), key enzymes required for replication. Ligand-based and structure-based virtual screening were combined with molecular docking , molecular dynamics (MD) simulations (100 ns) , and ADME/Tox profiling using contemporary computational tools (AutoDock Vina 1.2.0, PyRx 0.9.8, YASARA 21.12.24 with AMBER14 force field, SwissADME 2023). Among the screened FDA-approved compounds, saquinavir, a clinically established HIV protease inhibitor, exhibited the most stable interactions within the 3CLpro active site of both viruses, supported by docking scores of –10.7 kcal/mol (PEDV) and –9.3 kcal/mol (PDCoV), and RMSD stabilization at ∼2.8 Å during 100 ns MD simulation. While eravacycline and irinotecan displayed slightly more negative docking energies, saquinavir was prioritized due to its mechanistic relevance as a protease inhibitor, superior stability in MD trajectories, and established safety record. Comparative ADME/Tox analysis indicated predictable pharmacokinetics and manageable bioavailability challenges, amenable to formulation-based improvement. These findings position saquinavir as a translational lead candidate for veterinary antiviral development, bridging human and animal antiviral discovery under the One Health framework. This study also provides a validated computational workflow adaptable for emerging coronaviral infections in livestock and it is an example of how combining veterinary medicine and innovative drug repurposing can open new doors to protect animal health and strengthen food security.