4ocz | pdb_00004ocz

Crystal structure of human soluble epoxide hydrolase complexed with 1-(1-isobutyrylpiperidin-4-yl)-3-(4-(trifluoromethyl)phenyl)urea

spinqualitylabelsall models 4ocz, resolution 2.94Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4ocz 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: 2RU, MG, PO4 Related: 4od0 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 Diabetes is affecting the life of millions of people. A large proportion of diabetic patients suffer from severe complications such as neuropathic pain, and current treatments for these complications have deleterious side effects. Thus, alternate therapeutic strategies are needed. Recently, the elevation of epoxy-fatty acids through inhibition of soluble epoxide hydrolase (sEH) was shown to reduce diabetic neuropathic pain in rodents. In this report, we describe a series of newly synthesized sEH inhibitors with at least 5-fold higher potency and doubled residence time inside both the human and rodent sEH enzyme than previously reported inhibitors. These inhibitors also have better physical properties and optimized pharmacokinetic profiles. The optimized inhibitor selected from this new series displayed improved efficacy of almost 10-fold in relieving pain perception in diabetic neuropathic rats as compared to the approved drug, gabapentin, and previously published sEH inhibitors. Therefore, these new sEH inhibitors could be an attractive alternative to treat diabetic neuropathy in humans. Optimized inhibitors of soluble epoxide hydrolase improve in vitro target residence time and in vivo efficacy.,Lee KS, Liu JY, Wagner KM, Pakhomova S, Dong H, Morisseau C, Fu SH, Yang J, Wang P, Ulu A, Mate CA, Nguyen LV, Hwang SH, Edin ML, Mara AA, Wulff H, Newcomer ME, Zeldin DC, Hammock BD J Med Chem. 2014 Aug 28;57(16):7016-30. doi: 10.1021/jm500694p. Epub 2014 Aug 11. PMID:25079952 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Epoxide hydrolase

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