5FP0

ligand complex structure of soluble epoxide hydrolase

Summary for 5FP0

• Entry DOI: 10.2210/pdb5fp0/pdb
• Descriptor: BIFUNCTIONAL EPOXIDE HYDROLASE 2, DIMETHYL SULFOXIDE, N-cyclopentyl-2-[4-(trifluoromethyl)phenyl]-3H-benzimidazole-4-sulfonamide, ... (4 entities in total)
• Functional Keywords: hydrolase
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Cytoplasm: P34913
• Total number of polymer chains: 1
• Total formula weight: 62490.27

Authors

Xue, Y.,Olsson, T.,Johansson, C.A.,Oster, L.,Beisel, H.G.,Rohman, M.,Karis, D.,Backstrom, S. (deposition date: 2015-11-26, release date: 2016-03-02, Last modification date: 2024-05-08)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.35 Å)