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

## TL;DR

This study uses computer simulations to find natural compounds that may block proteins of two poultry viruses, offering a potential new way to control these diseases.

## Contribution

The study identifies natural inhibitors of FAdV-1 and FAdV-4 fiber proteins using integrated virtual screening and molecular dynamics.

## Key findings

- Three natural compounds showed strong binding to viral fiber proteins across multiple simulations.
- ANPDB_2908 bound to both FAdV-1 and FAdV-4 proteins, while others showed serotype-specific interactions.
- The compounds displayed favorable stability and drug-likeness for further development.

## Abstract

Viral diseases in poultry cause major economic losses worldwide and threaten food production. Two important viruses, known to damage the liver and digestive organs of chickens, spread rapidly between farms and are difficult to control. Current prevention methods mainly rely on vaccination and farm hygiene, but there are no specific antiviral treatments available if birds become infected. This study aimed to discover natural compounds that could potentially block key viral proteins responsible for the virus attaching to and entering chicken cells. Using advanced computer-based methods, we screened thousands of plant-derived molecules from African natural product collections to identify those most likely to bind strongly to these viral proteins. The most promising compounds were further evaluated for their stability, safety, and behavior in biological systems using predictive models. Several natural molecules showed strong and stable interactions with the viral targets and displayed characteristics suggesting they could be safe for further testing. While these findings are based on computer simulations and must still be confirmed in laboratory and animal studies, they provide an important first step toward developing new antiviral strategies for poultry. Such treatments could help reduce disease spread, limit economic losses for farmers, and contribute to more secure and sustainable poultry production worldwide.

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, ANPDB_6449 (−10.3 kcal/mol), ANPDB_2908 (−10.2 and −10.0 kcal/mol), and SANCDB_245 (−9.2 kcal/mol), consistently emerged as strong candidates across the entire computational workflow. While ANPDB_2908 demonstrated notable multi-target capability by binding to fiber proteins from both FAdV-1 and FAdV-4, ANPDB_6449 and SANCDB_245 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.