Discovery of novel wee1 inhibitors via structure-based virtual screening and biological evaluation.
J Comput Aided Mol Des
; 32(9): 901-915, 2018 09.
Article
em En
| MEDLINE
| ID: mdl-30182144
ABSTRACT
Wee1 plays a critical role in the arrest of G2/M cell cycle for DNA repair before entering mitosis. Many cancer cells have been identified as overexpression of Wee1. In this research, pharmacophore modeling, molecular docking and molecular dynamics simulation approaches were constructed to identify novel potential Wee1 inhibitors. A compound 8 was found to have a novel skeleton against Wee1 with an IC50 value of 22.32 µM and a Ki value of 13.11 µM. Kinetic assays were employed to evaluate the compound 8 as a competitive inhibitor. Compound 8 was tested against A-549 tumor cell lines with IC50 value of 17.8 µM. To investigate the intermolecular interaction of Wee1 and compound 8, further molecular dynamics simulations were performed. It indicates that the binding mode of compound 8 and reference ligand is similar. The active core scaffold of compound 8 could represent a promising lead compound for studying Wee1 and be used for further structural optimization to design more potent Wee1 inhibitors.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proteínas Tirosina Quinases
/
Proteínas Nucleares
/
Proteínas de Ciclo Celular
/
Inibidores de Proteínas Quinases
Tipo de estudo:
Diagnostic_studies
/
Screening_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article