Discovery of a novel class of non-ATP site DFG-out state p38 inhibitors utilizing computationally assisted virtual fragment-based drug design (vFBDD).
Bioorg Med Chem Lett
; 21(23): 7155-65, 2011 Dec 01.
Article
en En
| MEDLINE
| ID: mdl-22014550
ABSTRACT
Discovery of a new class of DFG-out p38α kinase inhibitors with no hinge interaction is described. A computationally assisted, virtual fragment-based drug design (vFBDD) platform was utilized to identify novel non-aromatic fragments which make productive hydrogen bond interactions with Arg 70 on the αC-helix. Molecules incorporating these fragments were found to be potent inhibitors of p38 kinase. X-ray co-crystal structures confirmed the predicted binding modes. A lead compound was identified as a potent (p38α IC(50)=22 nM) and highly selective (≥ 150-fold against 150 kinase panel) DFG-out p38 kinase inhibitor.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Oligopéptidos
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Tiofenos
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Simulación por Computador
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Proteínas Quinasas p38 Activadas por Mitógenos
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Inhibidores Enzimáticos
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Descubrimiento de Drogas
Tipo de estudio:
Prognostic_studies
Límite:
Animals
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Humans
Idioma:
En
Año:
2011
Tipo del documento:
Article