2p4j: Difference between revisions
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'''Crystal structure of beta-secretase bond to an inhibitor with Isophthalamide Derivatives at P2-P3''' | '''Crystal structure of beta-secretase bond to an inhibitor with Isophthalamide Derivatives at P2-P3''' | ||
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[[Category: Hong, L.]] | [[Category: Hong, L.]] | ||
[[Category: Tang, J.]] | [[Category: Tang, J.]] | ||
[[Category: | [[Category: Acid protease]] | ||
[[Category: | [[Category: Alzheimer's disease]] | ||
[[Category: | [[Category: Asp]] | ||
[[Category: | [[Category: Aspartic protease]] | ||
[[Category: | [[Category: Bace]] | ||
[[Category: | [[Category: Beta-secretase]] | ||
[[Category: | [[Category: Drug design]] | ||
[[Category: | [[Category: Memapsin]] | ||
[[Category: | [[Category: Structure based drug design]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 12:20:40 2008'' | |||
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Revision as of 12:20, 4 May 2008
Crystal structure of beta-secretase bond to an inhibitor with Isophthalamide Derivatives at P2-P3
OverviewOverview
Structure-based design and synthesis of a number of potent and selective memapsin 2 inhibitors are described. These inhibitors were designed based upon the X-ray structure of memapsin 2-bound inhibitor 3 that incorporates methylsulfonyl alanine as the P2-ligand and a substituted pyrazole as the P3-ligand. Of particular importance, we examined the ability of the substituted isophthalic acid amide derivative to mimic the key interactions in the S2-S3 regions of the enzyme active sites of 3-bound memapsin 2. We investigated various substituted phenylethyl, alpha-methylbenzyl, and oxazolylmethyl groups as the P3-ligands. A number of inhibitors exhibited very potent inhibitory activity against mempasin 2 and good selectivity against memapsin 1. Inhibitor 5d has shown low nanomolar enzyme inhibitory potency (Ki=1.1 nM) and very good cellular inhibitory activity (IC50=39 nM). Furthermore, in a preliminary study, inhibitor 5d has shown 30% reduction of Abeta40 production in transgenic mice after a single intraperitoneal administration (8 mg/kg). A protein-ligand X-ray crystal structure of 5d-bound memapsin 2 provided vital molecular insight that can serve as an important guide to further design of novel inhibitors.
About this StructureAbout this Structure
2P4J is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
ReferenceReference
Design, synthesis, and X-ray structure of potent memapsin 2 (beta-secretase) inhibitors with isophthalamide derivatives as the P2-P3-ligands., Ghosh AK, Kumaragurubaran N, Hong L, Kulkarni SS, Xu X, Chang W, Weerasena V, Turner R, Koelsch G, Bilcer G, Tang J, J Med Chem. 2007 May 17;50(10):2399-407. Epub 2007 Apr 14. PMID:17432843 Page seeded by OCA on Sun May 4 12:20:40 2008