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PDBsum entry 3vv8
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Hydrolase/hydrolase inhibitor
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PDB id
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3vv8
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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 beta secetase in complex with 2-amino-3-methyl-6- ((1s,2r)-2-(3'-methylbiphenyl-4-yl)cyclopropyl)pyrimidin-4(3h)-one
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Structure:
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Beta-secretase 1. Chain: a. Fragment: unp residues 43-454. 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: bace1. Expressed in: escherichia coli. Expression_system_taxid: 562.
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Resolution:
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2.50Å
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R-factor:
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0.227
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R-free:
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0.287
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Authors:
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S.Yonezawa,T.Yamamoto,H.Yamakawa,C.Muto,M.Hosono,K.Hattori, K.Higashino,M.Sakagami,H.Togame,Y.Tanaka,T.Nakano,H.Takemoto, M.Arisawa,S.Shuto
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Key ref:
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S.Yonezawa
et al.
(2012).
Conformational restriction approach to β-secretase (BACE1) inhibitors: effect of a cyclopropane ring to induce an alternative binding mode.
J Med Chem,
55,
8838-8858.
PubMed id:
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Date:
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17-Jul-12
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Release date:
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24-Oct-12
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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.
358 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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J Med Chem
55:8838-8858
(2012)
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PubMed id:
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Conformational restriction approach to β-secretase (BACE1) inhibitors: effect of a cyclopropane ring to induce an alternative binding mode.
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S.Yonezawa,
T.Yamamoto,
H.Yamakawa,
C.Muto,
M.Hosono,
K.Hattori,
K.Higashino,
T.Yutsudo,
H.Iwamoto,
Y.Kondo,
M.Sakagami,
H.Togame,
Y.Tanaka,
T.Nakano,
H.Takemoto,
M.Arisawa,
S.Shuto.
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ABSTRACT
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Improvement of a drug's binding activity using the conformational restriction
approach with sp(3) hybridized carbon is becoming a key strategy in drug
discovery. We applied this approach to BACE1 inhibitors and designed four
stereoisomeric cyclopropane compounds in which the ethylene linker of a known
amidine-type inhibitor 2 was replaced with chiral cyclopropane rings. The
synthesis and biologic evaluation of these compounds revealed that the
cis-(1S,2R) isomer 6 exhibited the most potent BACE1 inhibitory activity among
them. X-ray structure analysis of the complex of 6 and BACE1 revealed that its
unique binding mode is due to the apparent CH-π interaction between the rigid
cyclopropane ring and the Tyr71 side chain. A derivatization study using 6 as a
lead molecule led to the development of highly potent inhibitors in which the
structure-activity relationship as well as the binding mode of the compounds
clearly differ from those of known amidine-type inhibitors.
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Links
