4Y2R

Structure of soluble epoxide hydrolase in complex with 2-(piperazin-1-yl)nicotinonitrile

Summary for 4Y2R

• Entry DOI: 10.2210/pdb4y2r/pdb
• Related: 4Y2J 4Y2P 4Y2Q 4Y2S 4Y2T 4Y2U 4Y2V 4Y2X 4Y2Y
• Descriptor: Bifunctional epoxide hydrolase 2, MAGNESIUM ION, 2-(piperazin-1-yl)pyridine-3-carbonitrile, ... (4 entities in total)
• Functional Keywords: hydrolase, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 63727.05

Authors

Amano, Y.,Yamaguchi, T. (deposition date: 2015-02-10, release date: 2015-05-06, Last modification date: 2023-11-08)

Primary citation

Amano, Y.,Tanabe, E.,Yamaguchi, T.
Identification of N-ethylmethylamine as a novel scaffold for inhibitors of soluble epoxide hydrolase by crystallographic fragment screening
Bioorg.Med.Chem., 23:2310-2317, 2015

PubMed 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.

PubMed: 25862210
DOI: 10.1016/j.bmc.2015.03.083

Experimental method

X-RAY DIFFRACTION (2.45 Å)