2p4j: Difference between revisions

Revision as of 19:25, 28 July 2008

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File:2p4j.png

Template:STRUCTURE 2p4j

Crystal structure of beta-secretase bond to an inhibitor with Isophthalamide Derivatives at P2-P3Crystal structure of beta-secretase bond to an inhibitor with Isophthalamide Derivatives at P2-P3

Template:ABSTRACT PUBMED 17432843

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

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Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA

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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===
-==Overview==
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-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.
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 ==About this Structure==
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 [[Category: Memapsin]]
 [[Category: Structure based drug design]]
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