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2fdp
From Proteopedia
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[[Image:2fdp.gif|left|200px]] | [[Image:2fdp.gif|left|200px]] | ||
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'''Crystal structure of beta-secretase complexed with an amino-ethylene inhibitor''' | '''Crystal structure of beta-secretase complexed with an amino-ethylene inhibitor''' | ||
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[[Category: Yang, W.]] | [[Category: Yang, W.]] | ||
[[Category: Zhong, M.]] | [[Category: Zhong, M.]] | ||
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| - | [[Category: | + | [[Category: Bace]] |
| - | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 03:46:24 2008'' | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | |
Revision as of 00:46, 4 May 2008
Crystal structure of beta-secretase complexed with an amino-ethylene inhibitor
Overview
A series of novel beta-site amyloid precursor protein cleaving enzyme (BACE-1) inhibitors containing an aminoethylene (AE) tetrahedral intermediate isostere were synthesized and evaluated in comparison to corresponding hydroxyethylene (HE) compounds. Enzymatic inhibitory values were similar for both isosteres, as were structure-activity relationships with respect to stereochemical preference and substituent variation (P2/P3, P1, and P2'); however, the AE compounds were markedly more potent in a cell-based assay for reduction of beta-secretase activity. The incorporation of preferred P2/P3, P1, and P2' substituents into the AE pharmacophore yielded compound 7, which possessed enzymatic and cell assay IC(50)s of 26 nM and 180 nM, respectively. A three-dimensional crystal structure of 7 in complex with BACE-1 revealed that the amino group of the inhibitor core engages the catalytic aspartates in a manner analogous to hydroxyl groups in HE inhibitors. The AE isostere class represents a promising advance in the development of BACE-1 inhibitors.
About this Structure
2FDP is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Aminoethylenes: a tetrahedral intermediate isostere yielding potent inhibitors of the aspartyl protease BACE-1., Yang W, Lu W, Lu Y, Zhong M, Sun J, Thomas AE, Wilkinson JM, Fucini RV, Lam M, Randal M, Shi XP, Jacobs JW, McDowell RS, Gordon EM, Ballinger MD, J Med Chem. 2006 Feb 9;49(3):839-42. PMID:16451048 Page seeded by OCA on Sun May 4 03:46:24 2008
Categories: Homo sapiens | Memapsin 2 | Single protein | Ballinger, M D. | Fucini, R V. | Gordon, E M. | Jacobs, J W. | Lam, M. | Lu, W. | Lu, Y. | McDowell, R S. | Randal, M. | Shi, X P. | Sun, J. | Thomas, A E. | Wilkinson, J M. | Yang, W. | Zhong, M. | Aspartyl protease | Bace
