Discovery of Leukotriene A4 Hydrolase Inhibitors Using Metabolomics Biased Fragment Crystallography
| Autor: | Alex B. Burgin, Magnus H. Haraldsson, Brian Pease, Hidong Kim, Douglas R. Davies, Lance Stewart, David E. Zembower, Rama K. Mishra, Alex S. Kiselyov, Jasbir Singh, Jeff Christensen, Mark E. Gurney, Olafur T. Magnusson, Bjorn Mamat, Erik C Hansen |
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| Rok vydání: | 2009 |
| Předmět: |
Stereochemistry
Allosteric regulation Crystallography X-Ray 010402 general chemistry 01 natural sciences Article Leukotriene-A4 hydrolase Structure-Activity Relationship 03 medical and health sciences Drug Discovery Hydrolase Humans Metabolomics Structure–activity relationship Enzyme Inhibitors Binding site 030304 developmental biology Epoxide Hydrolases Indole test 0303 health sciences Binding Sites Drug discovery Chemistry Hydrogen Bonding Small molecule 0104 chemical sciences 3. Good health Crystallography Biochemistry Molecular Medicine |
| Zdroj: | Journal of Medicinal Chemistry |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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