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Predicting Blood-Brain Barrier Permeation of Erlotinib and JCN037 by Molecular Simulation.
Liang, Yanshu; Zhi, Shuang; Qiao, Zhixia; Meng, Fancui.
Afiliación
  • Liang Y; School of Mechanical Engineering, Tianjin University of Commerce, Tianjin, 300134, People's Republic of China. lyshu_tjcu@163.com.
  • Zhi S; Tianjin Institute of Medical and Pharmaceutical Sciences, Tianjin, 300020, People's Republic of China.
  • Qiao Z; School of Mechanical Engineering, Tianjin University of Commerce, Tianjin, 300134, People's Republic of China.
  • Meng F; State Key Laboratory of Drug Delivery Technology and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, Tianjin, 300301, People's Republic of China.
J Membr Biol ; 256(2): 147-157, 2023 04.
Article en En | MEDLINE | ID: mdl-36441253
ABSTRACT
Glioblastoma (GBM) is a highly malignant primary brain tumor, and epidermal growth factor receptor (EGFR) is a well characterized biomaker on GBM. Treatment of GBM with EGFR inhibitors achieved limited efficacy due to low blood-brain barrier (BBB) permeability, and BBB-penetrant drugs are required. In this study, the BBB penetration of erlotinib and JN037 were studied using molecular dynamics method with explicit membrane model. The free energy profiles indicate that JCN037 has a lower central energy barrier than erlotinib, and it has a local minimum at lipid-water interface while erlotinib has not. Unconstrained MD simulations found that erlotinib prefers staying in water while JCN037 tends to interact with lipid molecules. Further analysis reveals that the Br atom of JCN037 plays an important role in its interaction with lipid molecules, and the adjacent F atom enhances the interaction of Br. The two flexible methoxyethoxy chains of erlotinib are responsible for its poor penetration. Our computational results agree well with the experimental results, providing useful information in the design and improvement of drugs with good BBB permeation.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Barrera Hematoencefálica / Glioblastoma Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Humans Idioma: En Revista: J Membr Biol Año: 2023 Tipo del documento: Article

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Barrera Hematoencefálica / Glioblastoma Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Humans Idioma: En Revista: J Membr Biol Año: 2023 Tipo del documento: Article