5FP0

ligand complex structure of soluble epoxide hydrolase

5FP0 の概要

• エントリーDOI: 10.2210/pdb5fp0/pdb
• 分子名称: BIFUNCTIONAL EPOXIDE HYDROLASE 2, DIMETHYL SULFOXIDE, N-cyclopentyl-2-[4-(trifluoromethyl)phenyl]-3H-benzimidazole-4-sulfonamide, ... (4 entities in total)
• 機能のキーワード: hydrolase
• 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: 1
• 化学式量合計: 62490.27

構造登録者

Xue, Y.,Olsson, T.,Johansson, C.A.,Oster, L.,Beisel, H.G.,Rohman, M.,Karis, D.,Backstrom, S. (登録日: 2015-11-26, 公開日: 2016-03-02, 最終更新日: 2024-05-08)

主引用文献

Xue, Y.,Olsson, T.,Johansson, C.A.,Oster, L.,Beisel, H.,Rohman, M.,Karis, D.,Backstrom, S.
Fragment Screening of Soluble Epoxide Hydrolase for Lead Generation-Structure-Based Hit Evaluation and Chemistry Exploration.
Chemmedchem, 11:497-, 2016

PubMed Abstract: Soluble epoxide hydrolase (sEH) is involved in the regulation of many biological processes by metabolizing the key bioactive lipid mediator, epoxyeicosatrienoic acids. For the development of sEH inhibitors with improved physicochemical properties, we performed both a fragment screening and a high-throughput screening aiming at an integrated hit evaluation and lead generation. Followed by a joint dose-response analysis to confirm the hits, the identified actives were then effectively triaged by a structure-based hit-classification approach to three prioritized series. Two distinct scaffolds were identified as tractable starting points for potential lead chemistry work. The oxoindoline series bind at the right-hand side of the active-site pocket with hydrogen bonds to the protein. The 2-phenylbenzimidazole-4-sulfonamide series bind at the central channel with significant induced fit, which has not been previously reported. On the basis of the encouraging initial results, we envision that a new lead series with improved properties could be generated if a vector is found that could merge the cyclohexyl functionality of the oxoindoline series with the trifluoromethyl moiety of the 2-phenylbenzimidazole-4-sulfonamide series.

PubMed: 26845235
DOI: 10.1002/CMDC.201500575

実験手法

X-RAY DIFFRACTION (2.35 Å)