Download MendeleyFragment-Based Discovery of 6-Azaindazoles as Inhibitors of Bacterial DNA Ligase.
Howard, S., Amin, N., Benowitz, A.B., Chiarparin, E., Cui, H., Deng, X., Heightman, T.D., Holmes, D.J., Hopkins, A., Huang, J., Jin, Q., Kreatsoulas, C., Martin, A.C.L., Massey, F., Mccloskey, L., Mortenson, P.N., Pathuri, P., Tisi, D., Williams, P.A.(2013) ACS Med Chem Lett 4: 1208
- PubMed: 24900632
- DOI: https://doi.org/10.1021/ml4003277
- Primary Citation of Related Structures:
4CC5, 4CC6 - PubMed Abstract:
Herein we describe the application of fragment-based drug design to bacterial DNA ligase. X-ray crystallography was used to guide structure-based optimization of a fragment-screening hit to give novel, nanomolar, AMP-competitive inhibitors. The lead compound 13 showed antibacterial activity across a range of pathogens. Data to demonstrate mode of action was provided using a strain of S. aureus, engineered to overexpress DNA ligase.
Organizational Affiliation:
Astex Pharmaceuticals Inc., 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom.
