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|3ftx, resolution 1.96Å ()|
|Ligands:||, , , , ,|
|Gene:||LTA4H, LTA4 (Homo sapiens)|
|Related:||3fh7, 3fts, 3ftu, 3ftv, 3ftw, 3fty, 3ftz, 3fu0, 3fu3, 3fu5, 3fu6, 3fud, 3fue, 3fuf, 3fuh, 3fui, 3fuj, 3fuk, 3ful, 3fum, 3fun|
Leukotriene A4 hydrolase in complex with dihydroresveratrol and bestatin
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.
Discovery of Leukotriene A4 Hydrolase Inhibitors Using Metabolomics Biased Fragment Crystallography (dagger)., Davies DR, Mamat B, Magnusson OT, Christensen J, Haraldsson MH, Mishra R, Pease B, Hansen E, Singh J, Zembower D, Kim H, Kiselyov AS, Burgin AB, Gurney ME, Stewart LJ, J Med Chem. 2009 Jul 20. PMID:19618939
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
About this Structure
- Davies DR, Mamat B, Magnusson OT, Christensen J, Haraldsson MH, Mishra R, Pease B, Hansen E, Singh J, Zembower D, Kim H, Kiselyov AS, Burgin AB, Gurney ME, Stewart LJ. Discovery of Leukotriene A4 Hydrolase Inhibitors Using Metabolomics Biased Fragment Crystallography (dagger). J Med Chem. 2009 Jul 20. PMID:19618939 doi:10.1021/jm900259h