Structural Insights into the Binding Mode of a BLU-945 Analog with Wild-Type and Mutant EGFRs

Overcoming the acquired C797S mutation in nonsmall cell lung cancer (NSCLC) represents a great challenge for EGFR tyrosine kinase inhibitors (TKIs). BLU-945 is a promising fourth-generation EGFR TKI undergoing clinical trials, with different binding conformation from other known EGFR TKIs. In this study, we explored the binding mode of a BLU-945 analog (BLU) with wild-type and mutant EGFRs using mu s-scale molecular dynamics. The results show that Met793 at the hinge region is the critical binding site for BLU as observed in other known EGFR inhibitors. The occupancy of hydrogen bonds with Met793 is lower in wild-type EGFRs than in mutant EGFRs. Meanwhile, Thr854 contributes largely to the hydrogen bond formation for triple mutant EGFR compared to wild-type EGFR. Energy decomposition reveals that Leu718 and Leu844 dominate the energy contribution. T790M mutation plays an important role in BLU binding with wild-type and mutant EGFRs. Dynamic network analysis indicates that Arg841 behaves differently in triple mutant EGFR compared to wild-type, single and double mutant EGFRs, confirmed by further analysis of salt-bridge formation. Our study may provide beneficial information for developing fourth-generation EGFR TKIs.