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PDBsum entry 4lxk
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Hydrolase/hydrolase inhibitor
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PDB id
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4lxk
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PDB id:
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| Name: |
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Hydrolase/hydrolase inhibitor
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Title:
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Crystal structure of human beta secretase in complex with compound 11d
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Structure:
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Beta-secretase 1. Chain: a, b, c. Fragment: catalytic domain, unp residues 48-447. Synonym: aspartyl protease 2, asp2, asp 2, beta-site amyloid precursor protein cleaving enzyme 1, beta-site app cleaving enzyme 1, memapsin-2, membrane-associated aspartic protease 2. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: bace, bace1, kiaa1149. Expressed in: escherichia coli. Expression_system_taxid: 469008.
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Resolution:
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2.05Å
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R-factor:
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0.200
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R-free:
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0.224
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Authors:
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J.M.Rondeau,E.Bourgier
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Key ref:
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H.Rueeger
et al.
(2013).
Discovery of cyclic sulfoxide hydroxyethylamines as potent and selective β-site APP-cleaving enzyme 1 (BACE1) inhibitors: structure based design and in vivo reduction of amyloid β-peptides.
Bioorg Med Chem Lett,
23,
5300-5306.
PubMed id:
DOI:
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Date:
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30-Jul-13
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Release date:
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28-Aug-13
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PROCHECK
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Headers
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References
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P56817
(BACE1_HUMAN) -
Beta-secretase 1 from Homo sapiens
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Seq:
Struc:
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501 a.a.
376 a.a.
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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DOI no:
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Bioorg Med Chem Lett
23:5300-5306
(2013)
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PubMed id:
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Discovery of cyclic sulfoxide hydroxyethylamines as potent and selective β-site APP-cleaving enzyme 1 (BACE1) inhibitors: structure based design and in vivo reduction of amyloid β-peptides.
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H.Rueeger,
R.Lueoend,
R.Machauer,
S.J.Veenstra,
L.H.Jacobson,
M.Staufenbiel,
S.Desrayaud,
J.M.Rondeau,
H.Möbitz,
U.Neumann.
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ABSTRACT
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Previous structure based optimization in our laboratories led to the
identification of a novel, high-affinity cyclic sulfone
hydroxyethylamine-derived inhibitor such as 1 that lowers CNS-derived Aβ
following oral administration to transgenic APP51/16 mice. Herein we report SAR
development in the S3 and S2' subsites of BACE1 for cyclic sulfoxide
hydroxyethyl amine inhibitors, the synthetic approaches employed in this effort,
and in vivo data for optimized compound such as 11d.
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Links
