Comparing the effect of traditional and novel tyrosine kinase inhibitors for epidermal growth factor receptor exon 20 insertions by molecular dynamics simulation

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Background Exon 20 insertions of epidermal growth factor receptor (EGFR) exhibit varying sensitivity to traditional and novel tyrosine kinase inhibitors for non-small cell lung cancer. Methods Molecular dynamics simulations were used to investigate the structural dynamics of wild-type EGFR and three representative exon 20 insertion mutations: V769_D770insASV (ASV), D770_N771insSVD (SVD), and N773_insNPH (NPH). Furthermore, the binding mechanisms of osimertinib and mobocertinib were explored to understand their efficacy across different EGFR variants. Results In this study, we found that binding to osimertinib and mobocertinib changed the free energy landscapes for ASV-, SVD- and NPH- EGFR . Compared with osimertinib, mobocertinib occupies extra space at the back of K745 for the three mutants and forms a hydrogen bond with the gatekeeper residue (T793) using its isopropyl ester group on the pyrimidine ring. When binding to osimertinib, ASV- and SVD- EGFR still revealed two energy minima on their free energy landscapes, but with considerably less conformational probability distribution at collective variable 2 >1.00 Å. In contrast, mobocertinib eliminated the energy minima at collective variable 2 >1.00 Å while decreasing the K745–E762 salt bridge formation rates. Conclusions Mobocertinib outperforms osimertinib in targeting specific subtypes of EGFR exon 20 insertions, highlighting its ability to restore the inactive state of this protein.