Identification of Inhibitors of Protein Kinase B Using Fragment-Based Lead Discovery
Journal of Medicinal Chemistry2007Vol. 50(10), pp. 2293–2296
Citations Over TimeTop 10% of 2007 papers
Gordon Saxty, Steven J. Woodhead, Valério Berdini, Thomas G. Davies, Marcel L. Verdonk, Paul G. Wyatt, Robert G. Boyle, David Barford, Robert Downham, Michelle D. Garrett, Robin A. E. Carr
Abstract
Using fragment-based screening techniques, 5-methyl-4-phenyl-1H-pyrazole (IC50 80 microM) was identified as a novel, low molecular weight inhibitor of protein kinase B (PKB). Herein we describe the rapid elaboration of highly potent and ligand efficient analogues using a fragment growing approach. Iterative structure-based design was supported by protein-ligand structure determinations using a PKA-PKB "chimera" and a final protein-ligand structure of a lead compound in PKBbeta itself.
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