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.

Active-Site Flexibility and Substrate Specificity in a Bacterial Virulence Factor: Crystallographic Snapshots of an Epoxide Hydrolase

“…Knowledge of active-site flexibility and expansions also allowed us to improve our first generation Cif inhibitor, increasing the specificity and affinity for the next generation (Bahl et al, 2015a; Kitamura et al, 2016). Our study, along with others, highlights the possibility for inducible fit in this class of enzymes, greatly expanding the range of potential substrates, particularly among physiological signaling epoxides (Morisseau, 2013; Selvan and Anishetty, 2015; Xue et al, 2016). …”

Novel Potential Binding Sites for Selective Inhibitor Design of Human Soluble Epoxide Hydrolase

“…They chose to deposit 52 structures within the hsEH dataset, including those containing some ambiguities, such as dual conformations or multiple binding sites, to provide the additional structural information [43]. In 2016, Xue et al also used a similar approach to completely map the active-site pocket to gain a deeper knowledge of ligand interactions and to guide the rational structure-based drug design [44]. They obtained more than 50 structures of ligand complexes and through the analysis, they characterised preferred binding sites with some consensus hot-spots, in addition to the central channel.…”

“…They obtained more than 50 structures of ligand complexes and through the analysis, they characterised preferred binding sites with some consensus hot-spots, in addition to the central channel. They identi ed two scaffolds: oxoindoline and 2-phenylbenzidazole-4-sulfonamide as a new series for potential hsEH inhibitors [44].…”

“…The obtained complexes extended the structural knowledge about possible dual conformations or multiple binding sites. In 2016, Xue et al used a similar approach to completely map the active site pocket to gain a deeper knowledge of ligand interactions and to guide the rational structure-based drug design [44].…”

Probing the orientation of inhibitor and epoxy-eicosatrienoic acid binding in the active site of soluble epoxide hydrolase

“…[13, 16-21] Although these holo -structures helped us to design better inhibitors, [13] these structures provide little information on how substrates bind to sEH, particularly lcPUFA epoxides. In addition, the substrate bound sEH structure has not yet been solved.…”