Discovery of Leukotriene A4 Hydrolase Inhibitors Using Metabolomics Biased Fragment Crystallography

• Published in: Journal of medicinal chemistry Vol. 52; no. 15; pp. 4694 - 4715
• Main Authors: Davies, Douglas R, Mamat, Bjorn, Magnusson, Olafur T, Christensen, Jeff, Haraldsson, Magnus H, Mishra, Rama, Pease, Brian, Hansen, Erik, Singh, Jasbir, Zembower, David, Kim, Hidong, Kiselyov, Alex S, Burgin, Alex B, Gurney, Mark E, Stewart, Lance J
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 13.08.2009; Amer Chemical Soc
• Subjects: ARCHITECTURE; BASIC BIOLOGICAL SCIENCES; Binding Sites; Biological and medical sciences; BIOSYNTHESIS; Chemistry, Medicinal; CRYSTALLOGRAPHY; Crystallography, X-Ray; Drug Discovery - methods; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Epoxide Hydrolases - antagonists & inhibitors; Epoxide Hydrolases - chemistry; GENERAL AND MISCELLANEOUS//MATHEMATICS, COMPUTING, AND INFORMATION SCIENCE; Humans; Hydrogen Bonding; HYDROLASES; INDOLES; Life Sciences & Biomedicine; Medical sciences; Metabolomics; Miscellaneous; national synchrotron light source; NICOTINAMIDE; Pharmacology & Pharmacy; Pharmacology. Drug treatments; PROTEINS; Science & Technology; Structure-Activity Relationship; A HYDROLASE; ANTIINFLAMMATORY ACTIVITY; LEAD DISCOVERY; INTERMEDIARY METABOLISM; X-RAY; PROTEIN-PROTEIN INTERACTIONS; ALPHA-HELIX MIMETICS; POTENT INHIBITORS; SACCHAROMYCES-CEREVISIAE; B-4 RECEPTOR; Drug; Metabolomics; Benzophenone derivatives; Enzyme; Metabolite; Thiazole derivatives; Crystallography; Ketone; Fragment; Biological activity; Pyrrolidine derivatives; Stilbene derivatives; Research and development; Pyridine derivatives; Thiophene derivatives; hydrolase; Ether hydrolases; Hydrolases; Inhibitor; Leukotriene-A; Small molecule; Indole derivatives; Chemical synthesis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm900259h

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.