Computational Identification of Natural Inhibitors Targeting Fiber Proteins of FAdV-1 and FAdV-4 Through Integrated Virtual Screening and Molecular Dynamics Simulations

Fowl adenoviruses (FAdVs) represent a major threat to poultry health, with serotypes FAdV-1 and FAdV-4 causing adenoviral gizzard erosion (AGE) and hepatitis-hydropericardium syndrome (HHS), respectively. A wide variety of afflicted birds, including chicken, pigeon, and psittacine species, have been reported to carry aviadenoviruses. The disease is highly contagious and spreads rapidly between flocks and farms through vertical and horizontal transmission. In this study, we implemented a multi-stage computational drug-discovery pipeline to identify natural inhibitors of the viral fiber proteins for both FAdV-1 and FAdV-4. A curated library of 7523 natural compounds from the African Natural Products Database (ANPDB) and the South African Natural Compounds Database (SANCDB) was subjected to ADMET-based filtering, molecular docking, ADMET prediction, and 500 ns molecular dynamics simulations against four structural targets: Fiber-1 and Fiber-2 of FAdV-4, and the Short and Long Fibers of FAdV-1. Three ligands, ANPDB₆449 (−10. 3 kcal/mol), ANPDB₂908 (−10. 2 and −10. 0 kcal/mol), and SANCDB₂45 (−9. 2 kcal/mol), consistently emerged as strong candidates across the entire computational workflow. While ANPDB₂908 demonstrated notable multi-target capability by binding to fiber proteins from both FAdV-1 and FAdV-4, ANPDB₆449 and SANCDB₂45 exhibited strong serotype-specific potential, supported by stable interaction profiles and favorable drug-likeness characteristics. Together, these compounds highlight promising natural scaffolds for the development of targeted antiviral interventions against pathogenic FAdV serotypes.