Identification of Novel Plant-derived Inhibitors of the EGFR Kinase Domain Using vHTS, QSAR and Molecular Docking Approaches

Abstract

The epidermal growth factor receptor (EGFR) protein tyrosine kinase (PTK) is a crucial target in the pursuit of anti-tumor drug discovery. This study investigates 305 phytochemicals from five known anticancer plants (Anacardium occidentale, Annona muricata, Spondias mombin, Ocimum gratisimum, and Zingiber officinale) for their potential as EGFR kinase domain inhibitors. Through Virtual High Throughput Screening (vHTS), lead compounds were identified and subjected to ADMET filtering. A Quantitative Structure-Activity Relationship (QSAR) model was developed using bioassay data from the ChEMBL database, exhibiting strong statistical robustness and external validation. Molecular docking studies revealed interactions of lead compounds with critical residues within the EGFR ATP kinase domain. Actinidine, berberine, and corydaline demonstrated adherence to Lipinski's rule of five, indicating drug-likeness. Notably, actinidine forms hydrophobic interactions with Phe-856, while berberine establishes hydrogen bonds with Asp-855. Corydaline engages in extensive hydrophobic and hydrogen bond interactions within the ATP pocket of the EGFR kinase domain. These findings underscore the potential of actinidine, berberine, and corydaline as EGFR kinase domain inhibitors, supported by a robust QSAR model, marking progress in the search for novel anticancer agents targeting EGFR inhibition.