Fragment Screening of Soluble Epoxide Hydrolase for Lead Generation—Structure‐Based Hit Evaluation and Chemistry Exploration. (4th February 2016)

• Record Type: Journal Article
• Authors: Xue, Yafeng; Olsson, Thomas; Johansson, Carina A; Öster, Linda; Beisel, Hans‐Georg; Rohman, Mattias; Karis, David; Bäckström, Stefan
• Is Part Of: ChemMedChem. Volume 11:Number 5(2016)
• Page Start: 497
• Page End: 508
• Publication Date: 2016-02-04
• Subjects: drug discovery -- high-throughput screening -- inhibitors -- ligand complex structures -- soluble epoxide hydrolase; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201500575
• Languages: English
• ISSNs: 1860-7179

Abstract

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. Abstract : The screening room : Both fragment screening and high‐throughput screening are used in an integrated hit‐finding and lead‐generation strategy. Two distinct scaffolds are identified as tractable starting points for further chemistry work. Significant induced‐fit binding is observed for the 2‐phenylbenzimidazole‐4‐sulfonamide compounds. A new lead series may be generated if features from the two series are combined together.