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

International Journal of Biological Macromolecules
Martiniano Bello

Abstract

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, ...Continue Reading

Citations

Dec 19, 2018·Journal of Biomolecular Structure & Dynamics·Lucia Saldaña-RiveraDavid Méndez-Luna
Dec 13, 2019·Journal of Computer-aided Molecular Design·Martiniano BelloRolando Alberto Rodriguez-Fonseca
Jul 10, 2019·Journal of Enzyme Inhibition and Medicinal Chemistry·Lianbao YeWeiqiang Chen
Aug 8, 2021·Journal of Molecular Modeling·Heberth de PaulaKathia Maria Honorio
Aug 29, 2021·Pharmaceuticals·Irving Balbuena-RebolledoMartiniano Bello

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