Binding Thermodynamics of Fourth-Generation EGFR Inhibitors Revealed by Absolute Binding Free Energy Calculations

The
overexpression or mutation of the kinase domain of the epidermal
growth factor receptor (EGFR) is strongly associated with non-small-cell
lung cancer (NSCLC). EGFR tyrosine kinase inhibitors (TKIs) have proven
to be effective in treating NSCLC patients. However, EGFR mutations
can result in drug resistance. To elucidate the mechanisms underlying
this resistance and inform future drug development, we examined the
binding affinities of BLU-945, a recently reported fourth-generation
TKI, to wild-type EGFR (EGFRWT) and its double-mutant (L858R/T790M;
EGFRDM) and triple-mutant (L858R/T790M/C797S; EGFRTM) forms. We compared the binding affinities of BLU-945, BLU-945 analogues, CH7233163 (another
fourth-generation TKI), and erlotinib (a first-generation TKI) using
absolute binding free energy calculations. Our findings reveal that
BLU-945 and CH7233163 exhibit binding affinities to both EGFRDM and EGFRTM stronger than those of erlotinib,
corroborating experimental data. We identified K745 and T854 as the
key residues in the binding of fourth-generation EGFR TKIs. Electrostatic
forces were the predominant driving force for the binding of fourth-generation
TKIs to EGFR mutants. Furthermore, we discovered that the incorporation
of piperidinol and sulfone groups in BLU-945 substantially enhanced
its binding capacity to EGFR mutants. Our study offers valuable theoretical
insights for optimizing fourth-generation EGFR TKIs.