title: Fragment Screening of Soluble Epoxide Hydrolase for Lead Generation-Structure-Based Hit Evaluation and Chemistry Exploration.
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.
authors: Department Discovery Sciences, AstraZeneca R&D Gothenburg, Pepparedsleden 1, 431 83, Mölndal, Sweden.
authors: Yafeng
authors: Y
authors: Xue
authors: Department Medicinal Chemistry, CVMD iMED, AstraZeneca R&D Gothenburg, Pepparedsleden 1, 431 83, Mölndal, Sweden.
authors: Thomas
authors: T
authors: Olsson
authors: Department Discovery Sciences, AstraZeneca R&D Gothenburg, Pepparedsleden 1, 431 83, Mölndal, Sweden.
authors: Carina A
authors: CA
authors: Johansson
authors: Department Discovery Sciences, AstraZeneca R&D Gothenburg, Pepparedsleden 1, 431 83, Mölndal, Sweden.
authors: Linda
authors: L
authors: Öster
authors: Department Medicinal Chemistry, CVMD iMED, AstraZeneca R&D Gothenburg, Pepparedsleden 1, 431 83, Mölndal, Sweden.
authors: Hans-Georg
authors: HG
authors: Beisel
authors: Department Discovery Sciences, AstraZeneca R&D Gothenburg, Pepparedsleden 1, 431 83, Mölndal, Sweden.
authors: Mattias
authors: M
authors: Rohman
authors: Department Medicinal Chemistry, CVMD iMED, AstraZeneca R&D Gothenburg, Pepparedsleden 1, 431 83, Mölndal, Sweden.
authors: David
authors: D
authors: Karis
authors: Department Discovery Sciences, AstraZeneca R&D Gothenburg, Pepparedsleden 1, 431 83, Mölndal, Sweden. yafeng.xue@astrazeneca.com.
authors: Stefan
authors: S
authors: Bäckström
mesh_terms: D020134:Catalytic Domain; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D057166:High-Throughput Screening Assays; D008958:Models, Molecular; D015394:Molecular Structure; D012995:Solubility
chemical_list: D004851:Epoxide Hydrolases
keywords: drug discovery; high-throughput screening; inhibitors; ligand complex structures; soluble epoxide hydrolase