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J Med Chem
; 55(21): 9195-207, 2012 Nov 08.
Artigo
em Inglês
| MEDLINE
| ID: mdl-22954357
RESUMO
The structure-based design, synthesis, and X-ray structure of protein-ligand complexes of exceptionally potent and selective ß-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.