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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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References listed in PDB file
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Key reference
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Title
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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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Authors
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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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Ref.
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J Med Chem, 2012,
55,
9069-9088.
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PubMed id
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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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Secondary reference #1
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Title
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High yield expression of human bace constructs in eschericia coli for refolding, Purification, And high resolution diffracting crystal forms.
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Authors
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A.G.Tomasselli,
D.J.Paddock,
T.L.Emmons,
A.M.Mildner,
J.W.Leone,
J.M.Lull,
J.I.Cialdella,
D.B.Prince,
H.D.Fischer,
R.L.Heinrikson,
T.E.Benson.
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Ref.
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Protein Pept Lett, 2008,
15,
131-143.
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PubMed id
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