4OD0

Crystal structure of human soluble epoxide hydrolase complexed with 1-(1-propanoylpiperidin-4-yl)-3-[4-(trifluoromethoxy)phenyl]urea


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.92 Å
  • R-Value Free: 0.252 
  • R-Value Work: 0.193 
  • R-Value Observed: 0.196 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Optimized inhibitors of soluble epoxide hydrolase improve in vitro target residence time and in vivo efficacy.

Lee, K.S.Liu, J.Y.Wagner, K.M.Pakhomova, S.Dong, H.Morisseau, C.Fu, S.H.Yang, J.Wang, P.Ulu, A.Mate, C.A.Nguyen, L.V.Hwang, S.H.Edin, M.L.Mara, A.A.Wulff, H.Newcomer, M.E.Zeldin, D.C.Hammock, B.D.

(2014) J Med Chem 57: 7016-7030

  • DOI: https://doi.org/10.1021/jm500694p
  • Primary Citation of Related Structures:  
    4OCZ, 4OD0

  • PubMed Abstract: 

    Diabetes is affecting the life of millions of people. A large proportion of diabetic patients suffer from severe complications such as neuropathic pain, and current treatments for these complications have deleterious side effects. Thus, alternate therapeutic strategies are needed. Recently, the elevation of epoxy-fatty acids through inhibition of soluble epoxide hydrolase (sEH) was shown to reduce diabetic neuropathic pain in rodents. In this report, we describe a series of newly synthesized sEH inhibitors with at least 5-fold higher potency and doubled residence time inside both the human and rodent sEH enzyme than previously reported inhibitors. These inhibitors also have better physical properties and optimized pharmacokinetic profiles. The optimized inhibitor selected from this new series displayed improved efficacy of almost 10-fold in relieving pain perception in diabetic neuropathic rats as compared to the approved drug, gabapentin, and previously published sEH inhibitors. Therefore, these new sEH inhibitors could be an attractive alternative to treat diabetic neuropathy in humans.


  • Organizational Affiliation

    Department of Entomology and Nematology, UCD Comprehensive Cancer Center, University of California Davis , One Shields Avenue, Davis, California 95616, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Bifunctional epoxide hydrolase 2555Homo sapiensMutation(s): 0 
Gene Names: EPHX2
EC: 3.3.2.10 (PDB Primary Data), 3.1.3.76 (PDB Primary Data)
UniProt & NIH Common Fund Data Resources
Find proteins for P34913 (Homo sapiens)
Explore P34913 
Go to UniProtKB:  P34913
PHAROS:  P34913
GTEx:  ENSG00000120915 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP34913
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
2RV
Query on 2RV

Download Ideal Coordinates CCD File 
D [auth A]1-(1-propanoylpiperidin-4-yl)-3-[4-(trifluoromethoxy)phenyl]urea
C16 H20 F3 N3 O3
AAJMQTLFRTZCJK-UHFFFAOYSA-N
PO4
Query on PO4

Download Ideal Coordinates CCD File 
B [auth A]PHOSPHATE ION
O4 P
NBIIXXVUZAFLBC-UHFFFAOYSA-K
MG
Query on MG

Download Ideal Coordinates CCD File 
C [auth A]MAGNESIUM ION
Mg
JLVVSXFLKOJNIY-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
2RV BindingDB:  4OD0 Ki: 0.91 (nM) from 1 assay(s)
IC50: min: 3.7, max: 13 (nM) from 2 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.92 Å
  • R-Value Free: 0.252 
  • R-Value Work: 0.193 
  • R-Value Observed: 0.196 
  • Space Group: P 65 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 92.136α = 90
b = 92.136β = 90
c = 243.354γ = 120
Software Package:
Software NamePurpose
MAR345dtbdata collection
MOLREPphasing
REFMACrefinement
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2014-09-24
    Type: Initial release
  • Version 1.1: 2023-09-20
    Changes: Data collection, Database references, Derived calculations, Refinement description