PDBsum entry 4y2s

Oxidoreductase/oxidoreductase inhibitor

PDB id: 4y2s

Contents

Protein chain

546 a.a.

Ligands

49P

Metals

_MG

Waters ×71

References listed in PDB file

Key reference

• Title: Identification of n-Ethylmethylamine as a novel scaffold for inhibitors of soluble epoxide hydrolase by crystallographic fragment screening.
• Authors: Y.Amano, E.Tanabe, T.Yamaguchi.
• Ref.: Bioorg Med Chem Lett, 2015, 23, 2310-2317. [DOI no: 10.1016/j.bmc.2015.03.083]
• PubMed id: 25862210

Abstract

Soluble epoxide hydrolase (sEH) is a potential target for the treatment of inflammation and hypertension. X-ray crystallographic fragment screening was used to identify fragment hits and their binding modes. Eight fragment hits were identified via soaking of sEH crystals with fragment cocktails, and the co-crystal structures of these hits were determined via individual soaking. Based on the binding mode, N-ethylmethylamine was identified as a promising scaffold that forms hydrogen bonds with the catalytic residues of sEH, Asp335, Tyr383, and Tyr466. Compounds containing this scaffold were selected from an in-house chemical library and assayed. Although the starting fragment had a weak inhibitory activity (IC50: 800μM), we identified potent inhibitors including 2-({[2-(adamantan-1-yl)ethyl]amino}methyl)phenol exhibiting the highest inhibitory activity (IC50: 0.51μM). This corresponded to a more than 1500-fold increase in inhibitory activity compared to the starting fragment. Co-crystal structures of the hit compounds demonstrate that the binding of N-ethylmethylamine to catalytic residues is similar to that of the starting fragment. We therefore consider crystallographic fragment screening to be appropriate for the identification of weak but promising fragment hits.