Fragment-based library generation for the discovery of a peptidomimetic p53-Mdm4 inhibitor.
ACS Comb Sci
; 16(8): 393-6, 2014 Aug 11.
Article
em En
| MEDLINE
| ID: mdl-24983416
ABSTRACT
On the basis of our recently resolved first cocrystal structure of Mdm4 in complex with a small molecule inhibitor (PDB ID 3LBJ ), we devised an approach for the generation of potential Mdm4 selective ligands. We performed the Ugi four-component reaction (Ugi-4CR) in 96-well plates with an indole fragment, which is specially designed to mimic Trp23, a key amino acid for the interaction between p53 and Mdm4. Generally the reaction yielded mostly precipitates collected by 96-well filter plates. The best hit compound was found to be active and selective for Mdm4 (Ki=5 µM, 10-fold stronger than Mdm2). This initial hit may serve as the starting point for designing selective p53-Mdm4 inhibitor with higher affinity.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proteína Supressora de Tumor p53
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Proteínas Proto-Oncogênicas c-mdm2
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Peptidomiméticos
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Mapas de Interação de Proteínas
Limite:
Humans
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article