Phytocompounds as Potential EGFR Inhibitors for Glioblastoma Management: A Structure-Based Molecular Docking and Simulation Study

Introduction: Glioblastoma (GBM) is a highly aggressive brain cancer with limited therapeutic options. The epidermal growth factor receptor (EGFR) plays a critical role in tumor progression, making it a promising target for novel treatments. This study aimed to identify plant-derived phytochemicals as potential EGFR inhibitors to enhance the management of GBM. Methods: Computational approaches were utilized, including virtual screening of phytochemicals from the NPACT database against the EGFR crystal structure (PDB ID: 5XWD). Molecular docking, ADMET (absorption, distribution, metabolism, excretion, and toxicity) profiling, and 50 ns molecular dynamics (MD) simulations were performed to evaluate binding affinity, pharmacokinetic properties, and complex stability using metrics, such as root mean square deviation (RMSD), radius of gyration (Rg), and solvent-accessible surface area (SASA). Cytotoxicity was assessed against the SF-295 GBM cell line. Results: Three phytochemicals, 2,3-dihydrowithaferin A, strophanthidin, and 6,8-diprenyleriodictyol, demonstrated strong EGFR binding affinities (-8.5 to -7.9 kcal/mol), favorable drug-like properties, and optimal ADMET profiles. MD simulations confirmed stable binding for 2,3-dihydrowithaferin A and 6,8-diprenyleriodictyol, with low RMSD (<2.5 Å), compact Rg (<2.2 nm), and reduced SASA. Only 6,8-diprenyleriodictyol exhibited cytotoxicity against SF-295 GBM cells (Pa = 0.383). Discussion: The findings position 6,8-diprenyleriodictyol as a promising EGFR inhibitor due to its balanced binding affinity, pharmacokinetic profile, and selective cytotoxicity, potentially addressing limitations of current EGFR inhibitors like erlotinib in GBM. The stable binding and favorable ADMET properties suggest potential for CNS penetration; however, the P-glycoprotein substrate status warrants further investigation. However, there is a need for in vitro and in vivo validation to confirm its efficacy and selectivity. Conclusion: 6,8-Diprenyleriodictyol emerges as a lead candidate for EGFR-targeted GBM therapy, supported by its strong binding, favorable pharmacokinetics, and cytotoxicity against GBM cells. Further experimental studies are needed to validate its therapeutic potential and overcome challenges, such as BBB penetration.