Identification through structure-based methods of a bacterial NAD(+)-dependent DNA ligase inhibitor that avoids known resistance mutations.
Bioorg Med Chem Lett
; 24(1): 360-6, 2014 Jan 01.
Article
en En
| MEDLINE
| ID: mdl-24287382
In an attempt to identify novel inhibitors of NAD(+)-dependent DNA ligase (LigA) that are not affected by a known resistance mutation in the adenosine binding pocket, a detailed analysis of the binding sites of a variety of bacterial ligases was performed. This analysis revealed several similarities to the adenine binding region of kinases, which enabled a virtual screen of known kinase inhibitors. From this screen, a thienopyridine scaffold was identified that was shown to inhibit bacterial ligase. Further characterization through structure and enzymology revealed the compound was not affected by a previously disclosed resistance mutation in Streptococcus pneumoniae LigA, Leu75Phe. A subsequent medicinal chemistry program identified substitutions that resulted in an inhibitor with moderate activity across various Gram-positive bacterial LigA enzymes.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
ADN Ligasas
/
Streptococcus pneumoniae
/
Inhibidores Enzimáticos
Tipo de estudio:
Diagnostic_studies
Idioma:
En
Revista:
Bioorg Med Chem Lett
Asunto de la revista:
BIOQUIMICA
/
QUIMICA
Año:
2014
Tipo del documento:
Article
Pais de publicación:
Reino Unido