Molecular dynamics simulation and free energy analysis of EGFR resistance mutations: implications for the design of novel inhibitors

Abstract

The epidermal growth factor receptor (EGFR) represents one of the most promising targets for non-small cell lung cancer (NSCLC) therapy. However, the clinical efficacy of EGFR inhibitors is often constrained by drug resistance. EGFR resistance is primarily caused by amino acid mutations in the receptor, with common mutations such as T790M, L858R and C797S. To deeply understand the mechanism of EGFR resistance, in the present work, we employed molecular dynamics (MD) simulation to examine the interaction between the wild-type and several mutant EGFRs (including EGFR^L858R, EGFR^T797S, EGFR^T790M/L858R, EGFR^T797S/C797S and EGFR^{T797S/L858R/C797S}) and the known EGFR inhibitors (Gefitinib, Osimertinib and TQB3804). The present work demonstrates that TQB3804 exhibits strong affinity and inhibition effects against various mutant forms of EGFR, indicating its potential to overcome resistance. Moreover, computational analyses of HOMO–LUMO energy gap revealed that TQB3804 interacts more stably at the EGFR active site than Osimertinib. The present work provides a crucial theoretical foundation for understanding the mechanisms of EGFR inhibitors and their resistance, offering valuable guidance for future drug design.