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PDBsum entry 3fty
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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 leukotriene a4 hydrolase inhibitors using metabolomics biased fragment crystallography.
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Authors
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D.R.Davies,
B.Mamat,
O.T.Magnusson,
J.Christensen,
M.H.Haraldsson,
R.Mishra,
B.Pease,
E.Hansen,
J.Singh,
D.Zembower,
H.Kim,
A.S.Kiselyov,
A.B.Burgin,
M.E.Gurney,
L.J.Stewart.
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Ref.
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J Med Chem, 2009,
52,
4694-4715.
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PubMed id
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Abstract
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We describe a novel fragment library termed fragments of life (FOL) for
structure-based drug discovery. The FOL library includes natural small molecules
of life, derivatives thereof, and biaryl protein architecture mimetics. The
choice of fragments facilitates the interrogation of protein active sites,
allosteric binding sites, and protein-protein interaction surfaces for fragment
binding. We screened the FOL library against leukotriene A4 hydrolase (LTA4H) by
X-ray crystallography. A diverse set of fragments including derivatives of
resveratrol, nicotinamide, and indole were identified as efficient ligands for
LTA4H. These fragments were elaborated in a small number of synthetic cycles
into potent inhibitors of LTA4H representing multiple novel chemotypes for
modulating leukotriene biosynthesis. Analysis of the fragment-bound structures
also showed that the fragments comprehensively recapitulated key chemical
features and binding modes of several reported LTA4H inhibitors.
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