Double click reaction for the acquisition of a highly potent and selective mPTPB inhibitor.
ChemMedChem
; 5(12): 2051-6, 2010 Dec 03.
Article
em En
| MEDLINE
| ID: mdl-20957718
ABSTRACT
Tuberculosis (TB), which is caused by Mycobacterium tuberculosis (Mtb), is a major worldwide threat to public health. Mycobacterium protein tyrosine phosphataseâ
B (mPTPB) is a virulent phosphatase secreted by Mtb, which is essential for the survival and persistence of the bacterium in the host. Consequently, small-molecule inhibitors of mPTPB are expected to serve as anti-TB agents with a novel mode of action. Herein, we report the discovery of highly potent and selective mPTPB inhibitors using a novel, double Click chemistry strategy. The most potent mPTPB inhibitor from this approach possesses a K(i) value of 160â
nM and a >25-fold selectivity for mPTPB over 19 other protein tyrosine phosphatases (PTBs). Molecular docking study of the enzyme-inhibitor complex provides a rationale for the high potency and selectivity of the lead compound and reveals an unusual binding mode, which may guide further optimization effort.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas de Bactérias
/
Proteínas Tirosina Fosfatases
/
Inibidores Enzimáticos
/
Antituberculosos
Idioma:
En
Ano de publicação:
2010
Tipo de documento:
Article