Application of Fragment-Based Drug Discovery against DNA Gyraseâ
B.
Chempluschem
; 80(8): 1250-1254, 2015 Aug.
Article
em En
| MEDLINE
| ID: mdl-31973307
ABSTRACT
Bacterial resistance to antibiotics remains a serious threat to global health. The gyraseâ
B enzyme is a well-validated target for developing antibacterial drugs. Despite being an attractive target for antibiotic development, there are currently no gyraseâ
B inhibitory drugs on the market. A fragment screen using 1,800â
compounds identified 14â
fragments that bind to Escherichia coli (E.â
coli) gyraseâ
B. The detailed characterization of binding is described for all 14â
fragments. With the aid of X-ray crystallography, modifications on a low-affinity fragment (KD =253â
µM, IC50 =634â
µM) has led to the development of a new class of potent phenyl aminopyrazole inhibitors against E.â
coli gyraseâ
B (IC50 =160â
nM). The study presented here combines the use of a set of biophysical techniques including differential scanning fluorimetry, nuclear magnetic resonance, isothermal titration calorimetry, and X-ray crystallography to methodically identify, quantify, and optimize fragments into new chemical leads.
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Base de dados:
MEDLINE
Idioma:
En
Revista:
Chempluschem
Ano de publicação:
2015
Tipo de documento:
Article