Novel inhibitors of DNA gyrase: 3D structure based biased needle screening, hit validation by biophysical methods, and 3D guided optimization. A promising alternative to random screening.

摘要: Random screening provided no suitable lead structures in a search for novel inhibitors of the bacterial enzyme DNA gyrase. Therefore, an alternative approach had to be developed. Relying on detailed 3D structural information targeted ATP binding site, our combines as key techniques (1) silico potential low molecular weight inhibitors, (2) biased high throughput gyrase screen, (3) validation hits by biophysical methods, and (4) guided optimization process. When was performed, initial data set containing 350 000 compounds could reduced 3000 molecules. Testing these selected assay 150 clustered 14 classes. Seven classes validated true, that act site located subunit B: phenols, 2-amino-triazines, 4-amino-pyrimidines, 2-amino-pyrimidines, pyrrolopyrimidines, indazoles, 2-hydroxymethyl-indoles. The highly potent e. g., 3,4-disubstituted indazole 23 being 10 times more inhibitor than novobiocin (3).