Predicting Blood-Brain Barrier Permeation of Erlotinib and JCN037 by Molecular Simulation.
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.
Palabras clave
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