Binding Thermodynamics of Fourth-Generation EGFR Inhibitors Revealed by Absolute Binding Free Energy Calculations
The overexpression or mutation from the kinase domain from the epidermal growth factor receptor (EGFR) is strongly connected with non-small-cell cancer of the lung (NSCLC). EGFR tyrosine kinase inhibitors (TKIs) are actually good at treating NSCLC patients. However, EGFR mutations can lead to drug resistance. To elucidate the mechanisms underlying this resistance and inform future drug development, we examined the binding affinities of BLU-945, a lately reported 4th-generation TKI, to wild-type EGFR (EGFRWT) and it is 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 4th-generation TKI), and erlotinib (an initial-generation TKI) using absolute binding free energy calculations. Our findings demonstrate that BLU-945 and CH7233163 exhibit binding affinities to both EGFRDM and EGFRTM more powerful than individuals of erlotinib, corroborating experimental data. We identified K745 and T854 because the key residues within the binding of 4th-generation EGFR TKIs. Electrostatic forces were the predominant driving pressure for that binding of 4th-generation TKIs to EGFR mutants. In addition, we learned that the incorporation of piperidinol and sulfone groups in BLU-945 substantially enhanced its binding ability to EGFR mutants. Our study offers valuable theoretical insights for optimizing 4th-generation EGFR TKIs.