6yl4

Soluble epoxide hydrolase in complex with 3-((R)-3-(1-hydroxyureido)but-1-yn-1-yl)-N-((S)-3-phenyl-3-(4-trifluoromethoxy)phenyl)propyl)benzamide

spinqualitylabelsall models 6yl4, resolution 2.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6yl4 is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: OWW Gene: EPHX2 (HUMAN) Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [HYES_HUMAN] Bifunctional enzyme. The C-terminal domain has epoxide hydrolase activity and acts on epoxides (alkene oxides, oxiranes) and arene oxides. Plays a role in xenobiotic metabolism by degrading potentially toxic epoxides. Also determines steady-state levels of physiological mediators. The N-terminal domain has lipid phosphatase activity, with the highest activity towards threo-9,10-phosphonooxy-hydroxy-octadecanoic acid, followed by erythro-9,10-phosphonooxy-hydroxy-octadecanoic acid, 12-phosphonooxy-octadec-9Z-enoic acid, 12-phosphonooxy-octadec-9E-enoic acid, and p-nitrophenyl phospate. Publication Abstract from PubMed Inhibition of multiple enzymes of the arachidonic acid cascade leads to synergistic anti-inflammatory effects. Merging of 5-lipoxygenase (5-LOX) and soluble epoxide hydrolase (sEH) pharmacophores led to the discovery of a dual 5-LOX/sEH inhibitor, which was subsequently optimized in terms of potency toward both targets and metabolic stability. The optimized lead structure displayed cellular activity in human polymorphonuclear leukocytes, oral bioavailability, and target engagement in vivo and demonstrated profound anti-inflammatory and anti-fibrotic efficiency in a kidney injury model caused by unilateral ureteral obstruction in mice. These results pave the way for investigating the therapeutic potential of dual 5-LOX/sEH inhibitors in other inflammation- and fibrosis-related disease models. Design, Synthesis, and Structure-Activity Relationship Studies of Dual Inhibitors of Soluble Epoxide Hydrolase and 5-Lipoxygenase.,Hiesinger K, Kramer JS, Beyer S, Eckes T, Brunst S, Flauaus C, Wittmann SK, Weizel L, Kaiser A, Kretschmer SBM, George S, Angioni C, Heering J, Geisslinger G, Schubert-Zsilavecz M, Schmidtko A, Pogoryelov D, Pfeilschifter J, Hofmann B, Steinhilber D, Schwalm S, Proschak E J Med Chem. 2020 Oct 12. doi: 10.1021/acs.jmedchem.0c00561. PMID:33044073 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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