£€0€ €0€ €0€ €'`¢€ €¡€0€ €3FUE£€0€¢€0€ €Protein Data Bank¡€ €¡€0€ €ç¡€ ¢€¢€¡€0€ €PDB¡€¡€3FUE£€¡€0€ €Ù¡€¢€¤€¡€0€ €0€ € €0€0€ €¡€0€ €Davies£€ D.R.Davies¤€D.R.¡€0€ €¡€0€ €Ù¡€¢€¤€«€1€¤€0€ €1€ €dDiscovery of leukotriene A4 hydrolase inhibitors using metabolomics biased fragment crystallography.¡€0€ € €0€0€ €¡€0€ €Davies£€ D.R.Davies¤€D.R.0€ €¡€0€ €Mamat£€B.Mamat¤€B.0€ €¡€0€ € Magnusson£€ O.T.Magnusson¤€O.T.0€ €¡€0€ € Christensen£€ J.Christensen¤€J.0€ €¡€0€ € Haraldsson£€M.H.Haraldsson¤€M.H.0€ €¡€0€ €Mishra£€R.Mishra¤€R.0€ €¡€0€ €Pease£€B.Pease¤€B.0€ €¡€0€ €Hansen£€E.Hansen¤€E.0€ €¡€0€ €Singh£€J.Singh¤€J.0€ €¡€0€ €Zembower£€ D.Zembower¤€D.0€ €¡€0€ €Kim£€H.Kim¤€H.0€ €¡€0€ €Kiselyov£€ A.S.Kiselyov¤€A.S.0€ €¡€0€ €Burgin£€ A.B.Burgin¤€A.B.0€ €¡€0€ €Gurney£€ M.E.Gurney¤€M.E.0€ €¡€0€ €Stewart£€ L.J.Stewart¤€L.J.¢€ €0€ €1€¤€ J Med Chem¥€ J Med Chem €Journal of medicinal chemistry¡€0€ €¡€0€ €Ù¡€¢€ ¡€52¢€15£€4694-715¨€eng£€1€ €+\{¢€10.1021/jm900259h¥€ PMC2722745§€0€ €PDB Citation Status¡€¡€primary¢€0€¡€¡€0€ €Ù¡€¢€ ¢€0€¢€ €0€ €1€ €dDiscovery of leukotriene A4 hydrolase inhibitors using metabolomics biased fragment crystallography.¡€0€ €¡€0€ €Ù¡€¢€ £€‚ÜWe 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.¬€+\{¢€0€ €0€ €MLeukotriene A4 hydrolase in complex with fragment 5-chloroindole and bestatin¡€ HYDROLASE¢€@Mol_id: 1 Organism_scientific: Homo sapiens Organism_taxid: 9606£€‚ÁLeukotriene A4 hydrolase in complex with fragment 5-chloroindole and bestatin; Leukotriene A4 Hydrolase, LTA4H, Fragment crystallography, Fragments of Life, FOL, Alternative splicing, Cytoplasm, Hydrolase, Leukotriene biosynthesis, Metal-binding, Metalloprotease, Multifunctional enzyme, Polymorphism, Protease, Zinc; Mol_id: 1; Molecule: Leukotriene A-4 hydrolase; Chain: A; Synonym: Leukotriene A(4) hydrolase, LTA-4 hydrolase; EC number: 3.3.2.6;¡€0€0€ €¡€0€ €A£€1 Leukotriene A-4 hydrolase¨€¥€0€¢€0€ € Homo sapiens¡€human£€1€0€ €taxon¡€ €%†¥€0€ € €0€ €Homo¡€sapiens¡€ specified£€šEukaryota; Metazoa; Chordata; Craniata; Vertebrata; 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