Structure based optimization of chromen-based TNF-α converting enzyme (TACE) inhibitors on S1' pocket and their quantitative structure-activity relationship (QSAR) study.
Bioorg Med Chem
; 18(24): 8618-29, 2010 Dec 15.
Article
en En
| MEDLINE
| ID: mdl-21078557
A series of coumarin based TACE inhibitors were designed to bind in S1' pocket of TACE enzyme based on their docking study. Twelve analogues were synthesized and most of compounds were active in vitro TACE enzyme inhibition as well as cellular TNF-α inhibition. Among these, 15l effectively inhibited the production of serum TNF-α by oral administration at a dose of 30 mg/kg. Compound 15l also showed a good oral bioavailability at 42% and effectively inhibited paw edema in rat carrageenan model. Quantitative structure-activity relationship (QSAR) study using genetic function approximation technique (GFA) and docking study were performed to confirm the series of coumarin core TACE inhibitors. QSAR model have been evaluated internally and externally using test set prediction. Through docking study of each molecule, it is validated that the electrostatic descriptors from the QSAR equation could explain the importance of S1' pocket and the TACE inhibitory activity well.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Cumarinas
/
Relación Estructura-Actividad Cuantitativa
/
Proteínas ADAM
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Bioorg Med Chem
Asunto de la revista:
BIOQUIMICA
/
QUIMICA
Año:
2010
Tipo del documento:
Article
Pais de publicación:
Reino Unido