Structure-based design of highly selective ß-secretase inhibitors: synthesis, biological evaluation, and protein-ligand X-ray crystal structure.
J Med Chem
; 55(21): 9195-207, 2012 Nov 08.
Article
em En
| MEDLINE
| ID: mdl-22954357
ABSTRACT
The structure-based design, synthesis, and X-ray structure of protein-ligand complexes of exceptionally potent and selective ß-secretase inhibitors are described. The inhibitors are designed specifically to interact with S(1)' active site residues to provide selectivity over memapsin 1 and cathepsin D. Inhibitor 5 has exhibited exceedingly potent inhibitory activity (K(i) = 17 pM) and high selectivity over BACE 2 (>7000-fold) and cathepsin D (>250000-fold). A protein-ligand crystal structure revealed important molecular insight into these selectivities. These interactions may serve as an important guide to design selectivity over the physiologically important aspartic acid proteases.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Ácidos Ftálicos
/
Sulfonamidas
/
Secretases da Proteína Precursora do Amiloide
/
Amidas
/
Indóis
Limite:
Humans
Idioma:
En
Revista:
J Med Chem
Assunto da revista:
QUIMICA
Ano de publicação:
2012
Tipo de documento:
Article
País de afiliação:
Estados Unidos