Discovery of a new Mycobacterium tuberculosis thymidylate synthase X inhibitor with a unique inhibition profile.
Biochem Pharmacol
; 135: 69-78, 2017 07 01.
Article
en En
| MEDLINE
| ID: mdl-28359706
ABSTRACT
Tuberculosis (TB), mainly caused by Mycobacterium tuberculosis (Mtb), is an infection that is responsible for roughly 1.5 million deaths per year. The situation is further complicated by the wide-spread resistance to the existing first- and second-line drugs. As a result of this, it is urgent to develop new drugs to combat the resistant bacteria as well as have lower side effects, which can promote adherence to the treatment regimens. Targeting the de novo synthesis of thymidylate (dTMP) is an important pathway to develop drugs for TB. Although Mtb carries genes for two families of thymidylate synthases (TS), ThyA and ThyX, only ThyX is essential for its normal growth. Both enzymes catalyze the conversion of uridylate (dUMP) to dTMP but employ a different catalytic approach and have different structures. Also, ThyA is the only TS found in humans. This is the rationale for identifying selective inhibitors against ThyX. We exploited the NADPH oxidation to NADP+ step, catalyzed by ThyX, to develop a spectrophotometric biochemical assay. Success of the assay was demonstrated by its effectiveness (average Z'=0.77) and identification of selective ThyX inhibitors. The most potent compound is a tight-binding inhibitor with an IC50 of 710nM. Its mechanism of inhibition is analyzed in relation to the latest findings of ThyX mechanism and substrate and cofactor binding order.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Timidilato Sintasa
/
Inhibidores Enzimáticos
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Descubrimiento de Drogas
/
Mycobacterium tuberculosis
/
Antituberculosos
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
Biochem Pharmacol
Año:
2017
Tipo del documento:
Article
País de afiliación:
Bélgica