Download MendeleyElectron density guided fragment-based lead discovery of ketohexokinase inhibitors.
Gibbs, A.C., Abad, M.C., Zhang, X., Tounge, B.A., Lewandowski, F.A., Struble, G.T., Sun, W., Sui, Z., Kuo, L.C.(2010) J Med Chem 53: 7979-7991
- PubMed: 21033679
- DOI: https://doi.org/10.1021/jm100677s
- Primary Citation of Related Structures:
3NBW, 3NC2, 3NC9, 3NCA - PubMed Abstract:
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.
Organizational Affiliation:
Johnson & Johnson Pharmaceutical Research and Development, Welsh and McKean Roads, Spring House, Pennsylvania 19477, USA.
