Discovery of Potent Inhibitors of Soluble Epoxide Hydrolase by Combinatorial Library Design and Structure-Based Virtual Screening

• Published in: Journal of medicinal chemistry 2011-03, Vol.54 (5), p.1211-1222
• Main Authors: Xing, Li, McDonald, Joseph J, Kolodziej, Steve A, Kurumbail, Ravi G, Williams, Jennifer M, Warren, Chad J, O’Neal, Janet M, Skepner, Jill E, Roberds, Steven L
• Format: Article
• Language: English
• Subjects: Benzoxazoles - chemical synthesis; Benzoxazoles - chemistry; Combinatorial Chemistry Techniques; Crystallography, X-Ray; Drug Design; Enzyme Assays; Epoxide Hydrolases - antagonists & inhibitors; Epoxide Hydrolases - chemistry; Fluorometry; Hydrogen Bonding; Models, Molecular; Molecular Structure; Quantitative Structure-Activity Relationship; Small Molecule Libraries; Solubility
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm101382t

Structure-based virtual screening was applied to design combinatorial libraries to discover novel and potent soluble epoxide hydrolase (sEH) inhibitors. X-ray crystal structures revealed unique interactions for a benzoxazole template in addition to the conserved hydrogen bonds with the catalytic machinery of sEH. By exploitation of the favorable binding elements, two iterations of library design based on amide coupling were employed, guided principally by the docking results of the enumerated virtual products. Biological screening of the libraries demonstrated as high as 90% hit rate, of which over two dozen compounds were single digit nanomolar sEH inhibitors by IC50 determination. In total the library design and synthesis produced more than 300 submicromolar sEH inhibitors. In cellular systems consistent activities were demonstrated with biochemical measurements. The SAR understanding of the benzoxazole template provides valuable insights into discovery of novel sEH inhibitors as therapeutic agents.