2p4j
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(New page: 200px<br /> <applet load="2p4j" size="450" color="white" frame="true" align="right" spinBox="true" caption="2p4j, resolution 2.500Å" /> '''Crystal structure ...)
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Revision as of 21:14, 12 November 2007
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Crystal structure of beta-secretase bond to an inhibitor with Isophthalamide Derivatives at P2-P3
Overview
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 Structure
2P4J is a Single protein structure of sequence from Homo sapiens with 23I as ligand. Active as Memapsin 2, with EC number 3.4.23.46 Full crystallographic information is available from OCA.
Reference
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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