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Structure-based design of highly selective ?-secretase inhibitors: synthesis, biological evaluation, and protein-ligand X-ray crystal structure.

ABSTRACT: The structure-based design, synthesis, and X-ray structure of protein-ligand complexes of exceptionally potent and selective ?-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.

SUBMITTER: Ghosh AK

PROVIDER: S-EPMC3493683 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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Structure-based design of highly selective β-secretase inhibitors: synthesis, biological evaluation, and protein-ligand X-ray crystal structure.

Ghosh Arun K AK Venkateswara Rao Kalapala K Yadav Navnath D ND Anderson David D DD Gavande Navnath N Huang Xiangping X Terzyan Simon S Tang Jordan J

Journal of medicinal chemistry 20120906 21

The structure-based design, synthesis, and X-ray structure of protein-ligand complexes of exceptionally potent and selective β-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 rev ...[more]

PMID: 22954357

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