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PDBsum entry 3kn0
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References listed in PDB file
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Key reference
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Title
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Application of fragment-Based nmr screening, X-Ray crystallography, Structure-Based design, And focused chemical library design to identify novel microm leads for the development of nm bace-1 (beta-Site app cleaving enzyme 1) inhibitors.
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Authors
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Y.S.Wang,
C.Strickland,
J.H.Voigt,
M.E.Kennedy,
B.M.Beyer,
M.M.Senior,
E.M.Smith,
T.L.Nechuta,
V.S.Madison,
M.Czarniecki,
B.A.Mckittrick,
A.W.Stamford,
E.M.Parker,
J.C.Hunter,
W.J.Greenlee,
D.F.Wyss.
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Ref.
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J Med Chem, 2010,
53,
942-950.
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PubMed id
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Abstract
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Fragment-based NMR screening, X-ray crystallography, structure-based design, and
focused chemical library design were used to identify novel inhibitors for
BACE-1. A rapid optimization of an initial NMR hit was achieved by a combination
of NMR and a functional assay, resulting in the identification of an isothiourea
hit with a K(d) of 15 microM for BACE-1. NMR data and the crystal structure
revealed that this hit makes H-bond interactions with the two catalytic
aspartates, occupies the nonprime side region of the active site of BACE-1, and
extends toward the S3 subpocket (S3sp). A focused NMR-based search for
heterocyclic isothiourea isosteres resulted in several distinct classes of
BACE-1 active site directed compounds with improved chemical stability and
physicochemical properties. The strategy for optimization of the 2-aminopyridine
lead series to potent inhibitors of BACE-1 was demonstrated. The structure-based
design of a cyclic acylguanidine lead series and its optimization into nanomolar
BACE-1 inhibitors are the subject of the companion paper
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