Structural highlights
Disease
[KHK_HUMAN] Defects in KHK are the cause of fructosuria (FRUCT) [MIM:229800]. Benign defect of intermediary metabolism.[1] [2]
Publication Abstract from PubMed
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.
Electron density guided fragment-based lead discovery of ketohexokinase inhibitors.,Gibbs AC, Abad MC, Zhang X, Tounge BA, Lewandowski FA, Struble GT, Sun W, Sui Z, Kuo LC J Med Chem. 2010 Nov 25;53(22):7979-91. Epub 2010 Oct 29. PMID:21033679[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Trinh CH, Asipu A, Bonthron DT, Phillips SE. Structures of alternatively spliced isoforms of human ketohexokinase. Acta Crystallogr D Biol Crystallogr. 2009 Mar;65(Pt 3):201-11. Epub 2009, Feb 20. PMID:19237742 doi:S0907444908041115
- ↑ Bonthron DT, Brady N, Donaldson IA, Steinmann B. Molecular basis of essential fructosuria: molecular cloning and mutational analysis of human ketohexokinase (fructokinase). Hum Mol Genet. 1994 Sep;3(9):1627-31. PMID:7833921
- ↑ Gibbs AC, Abad MC, Zhang X, Tounge BA, Lewandowski FA, Struble GT, Sun W, Sui Z, Kuo LC. Electron density guided fragment-based lead discovery of ketohexokinase inhibitors. J Med Chem. 2010 Nov 25;53(22):7979-91. Epub 2010 Oct 29. PMID:21033679 doi:10.1021/jm100677s
