Structure Report for: 3WKE

Amano, Y., Yamaguchi, T., Tanabe, E.

Title: Structural insights into binding of inhibitors to soluble epoxide hydrolase gained by fragment screening and X-ray crystallography
Amano Y, Yamaguchi T, Tanabe E
Ref: Bioorganic & Medicinal Chemistry, 22:2427, 2014 : PubMed
Abstract


ESTHER: Amano_2014_Bioorg.Med.Chem_22_2427
PubMedSearch: Amano 2014 Bioorg.Med.Chem 22 2427
PubMedID: 24656800
Gene_locus related to this paper: human-EPHX2
Inhibitor(s) related to this paper: CHEMBL3233608-S0J-3WKC, CHEMBL2094355-S0I-3WKB, CHEMBL3233607-S0G-3WKA, CHEMBL3233606-S0F-3WK9, CHEMBL442384-S0E-3WK8, CHEMBL3233605-S0D-3WK7, ZINC527968-S0B-3WK6, CHEMBL3233604-S0C-3WK5, ZINC10109382-S0A-3WK4, CHEMBL3233609-S0K-3WKD, t-AUCB

Abstract

Soluble epoxide hydrolase (sEH) is a component of the arachidonic acid cascade and is a candidate target for therapies for hypertension or inflammation. Although many sEH inhibitors are available, their scaffolds are not structurally diverse, and knowledge of their specific interactions with sEH is limited. To obtain detailed structural information about protein-ligand interactions, we conducted fragment screening of sEH, analyzed the fragments using high-throughput X-ray crystallography, and determined 126 fragment-bound structures at high resolution. Aminothiazole and benzimidazole derivatives were identified as novel scaffolds that bind to the catalytic triad of sEH with good ligand efficiency. We further identified fragment hits that bound to subpockets of sEH called the short and long branches. The water molecule conserved in the structure plays an important role in binding to the long branch, whereas Asp496 and the main chain of Phe497 form hydrogen bonds with fragment hits in the short branch. Fragment hits and their crystal structures provide structural insights into ligand binding to sEH that will facilitate the discovery of novel and potent inhibitors of sEH.