Discovery of d-amino acid oxidase inhibitors based on virtual screening against the lid-open enzyme conformation.
Bioorg Med Chem Lett
; 28(10): 1693-1698, 2018 06 01.
Article
en En
| MEDLINE
| ID: mdl-29699925
ABSTRACT
d-Amino acid oxidase (DAAO) inhibitors are typically small polar compounds with often suboptimal pharmacokinetic properties. Features of the native binding site limit the operational freedom of further medicinal chemistry efforts. We therefore initiated a structure based virtual screening campaign based on the X-ray structures of DAAO complexes where larger ligands shifted the loop (lid opening) covering the native binding site. The virtual screening of our in-house collection followed by the in vitro test of the best ranked compounds led to the identification of a new scaffold with micromolar IC50. Subsequent SAR explorations enabled us to identify submicromolar inhibitors. Docking studies supported by in vitro activity measurements suggest that compounds bind to the active site with a salt-bridge characteristic to DAAO inhibitor binding. In addition, displacement of and interaction with the loop covering the active site contributes significantly to the activity of the most potent compounds.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
D-Aminoácido Oxidasa
/
Inhibidores Enzimáticos
/
Bibliotecas de Moléculas Pequeñas
/
Descubrimiento de Drogas
/
Amidas
Tipo de estudio:
Diagnostic_studies
/
Prognostic_studies
/
Screening_studies
Límite:
Humans
Idioma:
En
Revista:
Bioorg Med Chem Lett
Asunto de la revista:
BIOQUIMICA
/
QUIMICA
Año:
2018
Tipo del documento:
Article
País de afiliación:
Hungria