Electron Density Guided Fragment-Based Lead Discovery of Ketohexokinase Inhibitors
- J&J-PRD
A fragment-based drug design paradigm has been successfully applied in the discovery of lead series of ketohexokinase inhibitors. The paradigm consists of three iterations of design, synthesis, and X-ray crystallographic screening to progress low molecular weight fragments to leadlike compounds. Applying electron density of fragments within the protein binding site as defined by X-ray crystallography, one can generate target specific leads without the use of affinity data. Our approach contrasts with most fragment-based drug design methodology where solution activity is a main design guide. Herein we describe the discovery of submicromolar ketohexokinase inhibitors with promising druglike properties.
- Research Organization:
- Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
- Sponsoring Organization:
- USDOE
- OSTI ID:
- 1002926
- Journal Information:
- J. Med. Chem., Journal Name: J. Med. Chem. Journal Issue: (22) ; 11, 2010 Vol. 53; ISSN JMCMAR; ISSN 0022-2623
- Country of Publication:
- United States
- Language:
- ENGLISH
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