Rational design of allosteric inhibitors targeting C797S mutant EGFR in NSCLC: an integrative in silico and

Background: The emergence of the C797S mutation in the epidermal growth factor receptor (EGFR) significantly limits the efficacy of covalent inhibitors in treating non-small cell lung cancer (NSCLC). This study aimed to design and evaluate novel allosteric inhibitors targeting the C797S mutant EGFR using advanced in silico methodologies. Methods: Utilizing scaffold hopping techniques, a library of compounds was generated based on the known allosteric inhibitor EAI045. Virtual screening identified 44 top-scoring compounds with strong binding affinities for the C797S mutant EGFR. Molecular docking studies evaluated binding interactions, while the MM-GBSA method assessed binding free energies. Additionally, pharmacokinetic properties were analysed using Lipinski's rule of five, and the most promising compound, MK1, underwent molecular dynamics simulations followed by Results: A total of 12 heterocyclic scaffolds were derived from EAI045, and 44 top-scoring compounds were identified through virtual screening and MM-GBSA analysis. MK1 demonstrated the highest docking score and a ΔG_bind of -29.36 kcal/mol, with strong interactions involving residues such as LYS728 and MET793. MD simulations over 100 ns confirmed the stability of the MK1-EGFR complex, with RMSD values stabilizing post-50 ns and RMSF values consistently below 3 Å. Conclusion: The findings highlight MK1 as a promising candidate for the treatment of NSCLC harbouring the C797S mutation, providing valuable insights for future drug design and development strategies targeting mutant EGFR.