Binding mechanism of kinase inhibitors to EGFR and T790M, L858R and L858R/T790M mutants through structural and energetic analysis.

Experimental studies have demonstrated that L858R mutation in the EGF receptor (EGFR) confers tumor sensitivity whereas T790M and L858R/T790M mutations cause resistance to tyrosine kinase inhibitors in patients with non-small cell lung cancer. Theoretical studies have been carried out to try to clarify the structural and energetic details linked to acquired resistance to Gefitinib, Erlotinib or Lapatinib, however, some of these studies are contradictory with each other and with experimental reports and did not mention whether the study was performed by considering the inactive or active EGFR states. In this study, we combined structural data and molecular dynamic simulations coupled to a molecular mechanics generalized Born surface area approach to provide insight into the binding mechanism between three FDA-approved drugs (Erlotinib, Gefitinib and Lapatinib) that target the wild-type and T790M, L858R and L858R/T790M mutants of EGFR. Structural analysis showed that the drugs impact differently the conformational space of active and inactive EGFR. Energetic analysis pointed out that some ligands have better affinity for the inactive EGFR than the active EGFR state. Comparative analysis of the molecular recognition of Gefitinib, Erlotinib and Lapatinib provided insight into the drug sensitivity or resistance observed for the three FDA-approved drugs evaluated.