Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 55, Issue 21, Pages 9195-9207Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm3008823
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Funding
- National Institutes of Health [AG 18933]
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The structure-based design, synthesis, and X-ray structure of protein-ligand complexes of exceptionally potent and selective beta-secretase inhibitors are described. The inhibitors are designed specifically to interact with S-1' active site residues to provide selectivity over memapsin 1 and cathepsin D. Inhibitor 5 has exhibited exceedingly potent inhibitory activity (K-i = 17 pM) and high selectivity over BACE 2 (>7000-fold) and cathepsin D (>250000-fold). A protein ligand crystal structure revealed important molecular insight into these selectivities. These interactions may serve as an important guide to design selectivity over the physiologically important aspartic acid proteases.
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