title: Evaluation of structure-derived pharmacophore of soluble epoxide hydrolase inhibitors by virtual screening.
abstract: The soluble epoxide hydrolase (sEH) is an enzyme located downstream of the CYP 450 branch of the arachidonic acid cascade and can be linked to a number of indications, including cardiovascular disorders, diabetes and inflammatory processes. Numerous inhibitors (sEHI) have been reported, mostly based on urea or amide scaffolds. The search for valid bioisosteric replacements is an ongoing challenge in the discovery of sEHI. We developed a receptor-based pharmacophore model on the basis of 13 crystal structures of the sEH and performed a virtual screening for novel compounds. The virtual screening hits were verified in vitro proving the basic applicability of the model and leading to novel non-urea sEHI.
authors.affiliation: Institute of Pharmaceutical Chemistry, Johann Wolfgang Goethe University, ZAFES/OSF, Max-von-Laue-Strasse 9, D-60438 Frankfurt am Main, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Moser
authors.forename: Janosch
authors.initials: J
authors.lastname: Achenbach
authors.forename: Franca-Maria
authors.initials: FM
authors.lastname: Klingler
authors.forename: Buscató
authors.initials: B
authors.lastname: Estel la
authors.forename: Steffen
authors.initials: S
authors.lastname: Hahn
authors.forename: Ewgenij
authors.initials: E
authors.lastname: Proschak
mesh_terms: D000631:Aminopyridines / Q000138:chemical synthesis / Q000737:chemistry*; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors*; D008954:Models, Biological; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D000631:Aminopyridines; D004791:Enzyme Inhibitors; D004851:Epoxide Hydrolases