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PDBsum entry 3l5c
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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 of cyclic acylguanidines as highly potent and selective beta-Site amyloid cleaving enzyme (bace) inhibitors: part i--Inhibitor design and validation.
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Authors
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Z.Zhu,
Z.Y.Sun,
Y.Ye,
J.Voigt,
C.Strickland,
E.M.Smith,
J.Cumming,
L.Wang,
J.Wong,
Y.S.Wang,
D.F.Wyss,
X.Chen,
R.Kuvelkar,
M.E.Kennedy,
L.Favreau,
E.Parker,
B.A.Mckittrick,
A.Stamford,
M.Czarniecki,
W.Greenlee,
J.C.Hunter.
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Ref.
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J Med Chem, 2010,
53,
951-965.
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PubMed id
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Abstract
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A number of novel amidine containing heterocycles were designed to reproduce the
unique interaction pattern, revealed by X-ray crystallography, between the
BACE-1 catalytic diad and a weak NMR screening hit (3), with special attention
paid to maintaining the appropriate basicity and limiting the number of
H-bonding donors of these scaffolds. The iminohydantoin cores (10 and 23) were
examined first and found to interact with the catalytic diad in one of two
binding modes (A and B), each with the iminohydantoin core flipped 180 degrees
in relation to the other. The amidine structural motif within each core forms a
bidentate interaction with a different aspartic acid of the catalytic diad. Both
modes reproduced a highly conserved interaction pattern between the inhibitors
and the catalytic aspartates, as revealed by 3. Potent iminohydantoin BACE-1
inhibitors have been obtained, validating the molecular design as aspartyl
protease catalytic site inhibitors. Brain penetrant small molecule BACE
inhibitors with high ligand efficiencies have been discovered, enabling multiple
strategies for further development of these inhibitors into highly potent,
selective and in vivo efficacious BACE inhibitors.
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