Discovery of leukotriene A4 hydrolase inhibitors using metabolomics biased fragment crystallography.
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.
Davies
Douglas R
DR
deCODE biostructures, Inc., 7869 NE Day Road West, Bainbridge Island, Washington 98110, USA.
Mamat
Bjorn
B
Magnusson
Olafur T
OT
Christensen
Jeff
J
Haraldsson
Magnus H
MH
Mishra
Rama
R
Pease
Brian
B
Hansen
Erik
E
Singh
Jasbir
J
Zembower
David
D
Kim
Hidong
H
Kiselyov
Alex S
AS
Burgin
Alex B
AB
Gurney
Mark E
ME
Stewart
Lance J
LJ
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
D004791:Enzyme Inhibitors; D004851:Epoxide Hydrolases; C043134:leukotriene A4 hydrolase