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

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.

SUBMITTER: Ghosh AK

PROVIDER: S-EPMC2745614 | biostudies-literature | 2006 Apr

REPOSITORIES: biostudies-literature

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

Ghosh Arun K AK Kumaragurubaran Nagaswamy N Hong Lin L Lei Hui H Hussain Khaja Azhar KA Liu Chun-Feng CF Devasamudram Thippeswamy T Weerasena Vajira V Turner Robert R Koelsch Gerald G Bilcer Geoffrey G Tang Jordan J

Journal of the American Chemical Society 20060401 16

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 ...[more]

PMID: 16620080

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