3PDC

Crystal structure of hydrolase domain of human soluble epoxide hydrolase complexed with a benzoxazole inhibitor

3PDC の概要

• エントリーDOI: 10.2210/pdb3pdc/pdb
• 関連するPDBエントリー: 1S8O 1VJ5 1ZD2 3i28 3iIy
• 分子名称: Epoxide hydrolase 2, N-(5-chloro-1,3-benzoxazol-2-yl)-2-cyclopentylacetamide (3 entities in total)
• 機能のキーワード: epoxide hydrolase, hydrolase, hypertension, beta barrel, alpha/beta hydrolase fold; epoxide hydrolase fold, 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. has low phosphatase activity, binds mg2+, acetylation of lysine, cytoplasm; peroxisome, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm: P34913
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 79181.50

構造登録者

Kurumbail, R.G.,Williams, J.M. (登録日: 2010-10-22, 公開日: 2011-04-06, 最終更新日: 2023-09-06)

主引用文献

Xing, L.,McDonald, J.J.,Kolodziej, S.A.,Kurumbail, R.G.,Williams, J.M.,Warren, C.J.,O'Neal, J.M.,Skepner, J.E.,Roberds, S.L.
Discovery of potent inhibitors of soluble epoxide hydrolase by combinatorial library design and structure-based virtual screening.
J.Med.Chem., 54:1211-1222, 2011

PubMed Abstract: 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 IC(50) 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.

PubMed: 21302953
DOI: 10.1021/jm101382t

実験手法

X-RAY DIFFRACTION (2.6 Å)