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PDBsum entry 3udh
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Hydrolase/hydrolase inhibitor
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PDB id
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3udh
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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 bace with compound 1
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Structure:
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Beta-secretase 1. Chain: a. Fragment: unp residues 58-453. Synonym: bace, 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, bace, kiaa1149. Expressed in: escherichia coli. Expression_system_taxid: 469008.
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Resolution:
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1.70Å
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R-factor:
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0.198
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R-free:
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0.241
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Authors:
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I.V.Efremov,F.F.Vajdos,K.Borzilleri,S.Capetta,P.Dorff,J.Dutra, M.Mansour,C.Oborski,T.O'Connell,T.J.O'Sullivan,J.Pandit,H.Wang, J.Withka
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Key ref:
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I.V.Efremov
et al.
(2012).
Discovery and optimization of a novel spiropyrrolidine inhibitor of β-secretase (BACE1) through fragment-based drug design.
J Med Chem,
55,
9069-9088.
PubMed id:
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Date:
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28-Oct-11
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Release date:
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18-Apr-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.
394 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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*
PDB and UniProt seqs differ
at 6 residue positions (black
crosses)
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J Med Chem
55:9069-9088
(2012)
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PubMed id:
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Discovery and optimization of a novel spiropyrrolidine inhibitor of β-secretase (BACE1) through fragment-based drug design.
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I.V.Efremov,
F.F.Vajdos,
K.A.Borzilleri,
S.Capetta,
H.Chen,
P.H.Dorff,
J.K.Dutra,
S.W.Goldstein,
M.Mansour,
A.McColl,
S.Noell,
C.E.Oborski,
T.N.O'Connell,
T.J.O'Sullivan,
J.Pandit,
H.Wang,
B.Wei,
J.M.Withka.
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ABSTRACT
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The aspartyl protease β-secretase, or BACE, has been demonstrated to be a key
factor in the proteolytic formation of Aβ-peptide, a major component of plaques
in the brains of Alzheimer's disease (AD) patients, and inhibition of this
enzyme has emerged as a major strategy for pharmacologic intervention in AD. An
X-ray-based fragment screen of Pfizer's proprietary fragment collection has
resulted in the identification of a novel BACE binder featuring spiropyrrolidine
framework. Although exhibiting only weak inhibitory activity against the BACE
enzyme, the small compound was verified by biophysical and NMR-based methods as
a bona fide BACE inhibitor. Subsequent optimization of the lead compound,
relying heavily on structure-based drug design and computational prediction of
physiochemical properties, resulted in a nearly 1000-fold improvement in potency
while maintaining ligand efficiency and properties predictive of good
permeability and low P-gp liability.
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Links
