Proteomimetic libraries: design, synthesis, and evaluation of p53-MDM2 interaction inhibitors.
J Comb Chem
; 8(3): 315-25, 2006.
Article
em En
| MEDLINE
| ID: mdl-16677000
ABSTRACT
The p53-MDM2 interaction regulates p53-mediated cellular responses to DNA damage, and MDM2 is overexpressed in 7% of all cancers. Structure-based computational design was applied to this system to design libraries centered on a scaffold that projects side chain functionalities with distance and angular relationships equivalent to those seen in the MDM2 interacting motif of p53. A library of 173 such compounds was synthesized using solution phase parallel chemistry. The in vitro competitive ability of the compounds to block p53 peptide binding to MDM2 was determined using a fluorescence polarization competition assay. The most active compound bound with K(d) = 12 microM, and its binding was characterized by (15)N-(1)H HSQC NMR.
Buscar no Google
Base de dados:
MEDLINE
Assunto principal:
Desenho de Fármacos
/
Proteína Supressora de Tumor p53
/
Inibidores Enzimáticos
/
Proteínas Proto-Oncogênicas c-mdm2
Tipo de estudo:
Evaluation_studies
Idioma:
En
Ano de publicação:
2006
Tipo de documento:
Article