Your browser doesn't support javascript.
loading
Resistance to a tyrosine kinase inhibitor mediated by changes to the conformation space of the kinase.
Freire, Thales Souza; Caracelli, Ignez; Zukerman-Schpector, Julio; Friedman, Ran.
Afiliação
  • Freire TS; Department of Physics, Federal University of São Carlos, São Carlos-SP, Brazil.
  • Caracelli I; Department of Physics, Federal University of São Carlos, São Carlos-SP, Brazil.
  • Zukerman-Schpector J; Department of Chemistry, Federal University of São Carlos, São Carlos-SP, Brazil.
  • Friedman R; Department of Chemistry and Biomedical Sciences, Linnæus University, 391 82 Kalmar, Sweden. ran.friedman@lnu.se.
Phys Chem Chem Phys ; 25(8): 6175-6183, 2023 Feb 22.
Article em En | MEDLINE | ID: mdl-36752538
Gilteritinib is a highly selective and effective inhibitor of the FLT3/ITD mutated protein, and is used successfully in treating acute myeloid leukaemia (AML). Unfortunately, tumour cells gradually develop resistance to gilteritinib due to mutations in the molecular drug target. The atomistic details behind this observed resistance are not clear, since the protein structure of the complex is only available in the inactive state, while the drug binds better to the active state. To overcome this limitation, we used a computer-aided approach where we docked gilteritinib to the active site of FLT3/ITD and calculated the Gibbs free energy difference between the binding energies of the parental and mutant enzymes. These calculations agreed with experimental estimations for one mutation (F691L) but not the other (D698N). To further understand how these mutations operate, we used metadynamics simulations to study the conformational landscape of the activation process. Both mutants show a lower activation energy barrier which suggests that they are more likely to adopt an active state until inhibited, making the mutant enzymes more active. This suggests that a higher efficiency of tyrosine kinases contributes to resistance not only against type 2 but also against type 1 kinase inhibitors.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Inibidores de Proteínas Quinases Idioma: En Revista: Phys Chem Chem Phys Assunto da revista: BIOFISICA / QUIMICA Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Brasil País de publicação: Reino Unido

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Inibidores de Proteínas Quinases Idioma: En Revista: Phys Chem Chem Phys Assunto da revista: BIOFISICA / QUIMICA Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Brasil País de publicação: Reino Unido