Identification and binding mode of a novel Leishmania Trypanothione reductase inhibitor from high throughput screening.
PLoS Negl Trop Dis
; 12(11): e0006969, 2018 11.
Article
em En
| MEDLINE
| ID: mdl-30475811
ABSTRACT
Trypanothione reductase (TR) is considered to be one of the best targets to find new drugs against Leishmaniasis. This enzyme is fundamental for parasite survival in the host since it reduces trypanothione, a molecule used by the tryparedoxin/tryparedoxin peroxidase system of Leishmania to neutralize hydrogen peroxide produced by host macrophages during infection. In order to identify new lead compounds against Leishmania we developed and validated a new luminescence-based high-throughput screening (HTS) assay that allowed us to screen a library of 120,000 compounds. We identified a novel chemical class of TR inhibitors, able to kill parasites with an IC50 in the low micromolar range. The X-ray crystal structure of TR in complex with a compound from this class (compound 3) allowed the identification of its binding site in a pocket at the entrance of the NADPH binding site. Since the binding site of compound 3 identified by the X-ray structure is unique, and is not present in human homologs such as glutathione reductase (hGR), it represents a new target for drug discovery efforts.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Contexto em Saúde:
2_ODS3
/
3_ND
Problema de saúde:
2_enfermedades_transmissibles
/
3_zoonosis
Assunto principal:
Proteínas de Protozoários
/
Inibidores Enzimáticos
/
Leishmania
/
NADH NADPH Oxirredutases
/
Antiprotozoários
Tipo de estudo:
Diagnostic_studies
/
Screening_studies
Limite:
Humans
Idioma:
En
Revista:
PLoS Negl Trop Dis
Assunto da revista:
MEDICINA TROPICAL
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Itália