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J Am Chem Soc. 2006 Apr 26;128(16):5310-1.

Design, synthesis and X-ray structure of protein-ligand complexes: important insight into selectivity of memapsin 2 (beta-secretase) inhibitors.

Author information

1
Department of Chemistry, Purdue University, West Lafayette, Indiana 47907, USA. akghosh@purdue.edu

Abstract

Structure-based design, synthesis, and X-ray structure of protein-ligand complexes of memapsin 2 are described. The inhibitors are designed specifically to interact with S2- and S3-active site residues to provide selectivity over memapsin 1 and cathepsin D. Inhibitor 6 has exhibited exceedingly potent inhibitory activity against memapsin 2 and selectivity over memapsin 1 (>3800-fold) and cathepsin D (>2500-fold). A protein-ligand crystal structure revealed cooperative interactions in the S2- and S3-active sites of memapsin 2. These interactions may serve as an important guide to design selectivity over memapsin 1 and cathepsin D.

PMID:
16620080
PMCID:
PMC2745614
DOI:
10.1021/ja058636j
[Indexed for MEDLINE]
Free PMC Article

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