Design, synthesis, and evaluation of novel quinazoline derivatives as potent EGFR inhibitors: In silico and in vitro approaches.

BACKGROUND

The Epidermal Growth Factor Receptor (EGFR) is a transmembrane tyrosine kinase receptor whose overexpression is associated with the progression of various cancers. Quinazoline derivatives are well-established scaffolds in the design of EGFR inhibitors. This study aims to identify potent quinazoline-based EGFR inhibitors using a combination of computational and experimental methods.

METHODS

A library of 264 quinazoline derivatives was screened via molecular docking using Molegro Virtual Docker. The top three compounds with the most favorable binding energies were selected for further analysis. Molecular dynamics (MD) simulations were conducted using Amber16 to assess stability. Binding free energies were calculated using MMGBSA and thermodynamic integration (TI). ADMET properties were evaluated using SwissADME, pkCSM, and AI-based predictive models. In vitro cytotoxicity, apoptosis, and cell cycle assays were conducted on EGFR-overexpressing cell lines to validate computational findings.

RESULTS

Compound 1, identified as N-(2,4-dimethoxyphenyl)-2-((6-fluoro-2-(4-fluorophenyl)quinazolin-4-yl)thio)acetamide, exhibited the highest binding affinity (-134.34 kcal/mol) and most stable MD profile. It showed the most favorable MMGBSA binding energy (-37.86 kcal/mol), predominantly driven by van der Waals interactions and nonpolar solvation forces. Compound 1 also demonstrated superior convergence of thermodynamic parameters and RMSD/RMSF metrics. ADMET analysis revealed that Compound 1, despite having lower GI absorption, exhibited a better binding and safety profile than the reference compound. In vitro assays confirmed Compound 1's potent antiproliferative effect (5 % viability at 100 μM, IC50 ≈ 10 μM) and highest apoptosis rate (75 %).

CONCLUSION

The integrated computational and experimental approach confirms Compound 1 as a promising EGFR inhibitor, characterized by strong binding affinity, structural stability, and anticancer potential. Although ADMET profiling indicates challenges such as low oral absorption, Compound 1's superior target engagement supports its prioritization for further development.