Computational Modeling Virtual Screening and Molecular Dynamics Simulation of Epidermal Growth Factor Receptor (EGFR) in Zebrafish (Danio rerio)

The Epidermal Growth Factor Receptor (EGFR) is a transmembrane tyrosine kinase that plays a pivotal role in regulating cell proliferation, differentiation, and reproductive signalling in vertebrates. In teleost, EGFR signalling governs oocyte maturation and folliculogenesis; however, the structural dynamics and specific modulation of this receptor in aquaculture species remain largely unexplored. This study presents a comprehensive in silico characterization of the zebrafish (Danio rerio) EGFR to elucidate its structural properties and identify potential pharmacological modulators. Genomic analysis revealed that the zebrafish egfr gene spans 6,151 bp with a coding sequence of 3,573 bp, encoding a 1,191 amino acid protein. Subcellular localization prediction indicated a 99.9% probability of plasma membrane retention, anchored by a single transmembrane helix (residues 641–663). Using the advanced deep-learning system AlphaFold 3, a high-confidence three-dimensional structure was generated. The model exhibited excellent stereochemical quality, with 93.6% of residues in the most favoured regions of the Ramachandran plot and an overall ERRAT quality factor of 94.42%. High-throughput virtual screening of 2,143 FDA-approved compounds identified Risperidone (binding energy −10.04 kcal/mol) and Glisoxepide (−9.38 kcal/mol) as top-ranked antagonist and agonist candidates, respectively. Molecular dynamics (MD) simulations (100 ns) demonstrated that the Risperidone–EGFR complex maintained a rigid, stable conformation (RMSD ~2.5 Å), anchored by key interactions with Asp831 and Lys721. In contrast, the Glisoxepide–EGFR complex displayed bounded conformational flexibility (RMSD ~3.5 Å), consistent with agonist-mediated receptor activation. These findings provide the detailed structural blueprint of zebrafish EGFR and highlight the potential of repurposing FDA-approved drugs as non-hormonal agents to modulate growth and reproduction in aquaculture.