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PDBsum entry 4x8t
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Hydrolase/hydrolase inhibitor
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PDB id
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4x8t
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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 novel p1 groups for coagulation factor viia inhibition using fragment-Based screening.
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Authors
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D.L.Cheney,
J.M.Bozarth,
W.J.Metzler,
P.E.Morin,
L.Mueller,
J.A.Newitt,
A.H.Nirschl,
A.R.Rendina,
J.K.Tamura,
A.Wei,
X.Wen,
N.R.Wurtz,
D.A.Seiffert,
R.R.Wexler,
E.S.Priestley.
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Ref.
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J Med Chem, 2015,
58,
2799-2808.
[DOI no: ]
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PubMed id
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Abstract
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A multidisciplinary, fragment-based screening approach involving protein
ensemble docking and biochemical and NMR assays is described. This approach led
to the discovery of several structurally diverse, neutral surrogates for
cationic factor VIIa P1 groups, which are generally associated with poor
pharmacokinetic (PK) properties. Among the novel factor VIIa inhibitory
fragments identified were aryl halides, lactams, and heterocycles.
Crystallographic structures for several bound fragments were obtained, leading
to the successful design of a potent factor VIIa inhibitor with a neutral lactam
P1 and improved permeability.
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