Fragment screening and druggability assessment for the CBP/p300 KIX domain through protein-observed 19Fâ
NMR spectroscopy.
Angew Chem Int Ed Engl
; 54(12): 3735-9, 2015 Mar 16.
Article
en En
| MEDLINE
| ID: mdl-25651535
ABSTRACT
(19)Fâ
NMR spectroscopy of labeled proteins is a sensitive method for characterizing structure, conformational dynamics, higher-order assembly, and ligand binding. Fluorination of aromatic side chains has been suggested as a labeling strategy for small-molecule ligand discovery for protein-protein interaction interfaces. Using a model transcription factor binding domain of the CREB binding protein (CBP)/p300, KIX, we report the first full small-molecule screen using protein-observed (19)Fâ
NMR spectroscopy. Screening of 508 compounds and validation by (1)H-(15)N HSQCâ
NMR spectroscopy led to the identification of a minimal pharmacaphore for the MLL-KIX interaction site. Hit rate analysis for the CREB-KIX and MLL-KIX sites provided a metric to assess the ligandability or "druggability" of each interface informing future medicinal chemistry efforts. The structural information from the simplified spectra and data collection speed, affords a new screening tool for analysis of protein interfaces and discovery of small molecules.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Resonancia Magnética Nuclear Biomolecular
/
Proteína de Unión a CREB
/
Proteína p300 Asociada a E1A
Tipo de estudio:
Diagnostic_studies
/
Prognostic_studies
/
Screening_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Angew Chem Int Ed Engl
Año:
2015
Tipo del documento:
Article