title: Discovery of leukotriene A4 hydrolase inhibitors using metabolomics biased fragment crystallography.
abstract: 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.
authors.affiliation: deCODE biostructures, Inc., 7869 NE Day Road West, Bainbridge Island, Washington 98110, USA.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Davies
authors.forename: Bjorn
authors.initials: B
authors.lastname: Mamat
authors.forename: Olafur T
authors.initials: OT
authors.lastname: Magnusson
authors.forename: Jeff
authors.initials: J
authors.lastname: Christensen
authors.forename: Magnus H
authors.initials: MH
authors.lastname: Haraldsson
authors.forename: Rama
authors.initials: R
authors.lastname: Mishra
authors.forename: Brian
authors.initials: B
authors.lastname: Pease
authors.forename: Erik
authors.initials: E
authors.lastname: Hansen
authors.forename: Jasbir
authors.initials: J
authors.lastname: Singh
authors.forename: David
authors.initials: D
authors.lastname: Zembower
authors.forename: Hidong
authors.initials: H
authors.lastname: Kim
authors.forename: Alex S
authors.initials: AS
authors.lastname: Kiselyov
authors.forename: Alex B
authors.initials: AB
authors.lastname: Burgin
authors.forename: Mark E
authors.initials: ME
authors.lastname: Gurney
authors.forename: Lance J
authors.initials: LJ
authors.lastname: Stewart
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D055808:Drug Discovery / Q000379:methods*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D006860:Hydrogen Bonding; D055432:Metabolomics; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D004851:Epoxide Hydrolases; C043134:leukotriene A4 hydrolase