1ym2
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(New page: 200px<br /> <applet load="1ym2" size="450" color="white" frame="true" align="right" spinBox="true" caption="1ym2, resolution 2.05Å" /> '''Crystal structure o...)
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Revision as of 18:15, 12 November 2007
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Crystal structure of human beta secretase complexed with NVP-AUR200
Overview
Molecular modeling based on the X-ray crystal structure of the Tang-Ghosh, heptapeptide inhibitor 1 (OM99-2) of BACE led to the design and synthesis, of a series of constrained P(1)' analogues. A cyclopentane ring was, incorporated in 1 spanning the P(1)' Ala methyl group and the adjacent, methylene carbon atom of the chain. Progressive truncation at the, P(2)'-P(4)' sites led to a potent truncated analogue 5 with good, selectivity over Cathepsin D. Using the same backbone replacement concept, a series of cyclopentane, cyclopentanone, tetrahydrofuran, pyrrolidine, and pyrrolidinone analogues were synthesized with considerable variation, at the P and P' sites. The cyclopentanone and 2-pyrrolidinone analogues 45, and 57 showed low nM BACE inhibition. X-ray cocrystal structures of two, analogues 5 and 45 revealed excellent convergence with the original, inhibitor 1 structure while providing new insights into other interactions, which could be exploited for future modifications.
About this Structure
1YM2 is a Single protein structure of sequence from Homo sapiens with AUA as ligand. Active as Memapsin 2, with EC number 3.4.23.46 Full crystallographic information is available from OCA.
Reference
Structure-based design, synthesis, and memapsin 2 (BACE) inhibitory activity of carbocyclic and heterocyclic peptidomimetics., Hanessian S, Yun H, Hou Y, Yang G, Bayrakdarian M, Therrien E, Moitessier N, Roggo S, Veenstra S, Tintelnot-Blomley M, Rondeau JM, Ostermeier C, Strauss A, Ramage P, Paganetti P, Neumann U, Betschart C, J Med Chem. 2005 Aug 11;48(16):5175-90. PMID:16078837
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