4X6X

Human soluble epoxide hydrolase in complex with a three substituted cyclopropane derivative


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.222 
  • R-Value Work: 0.199 
  • R-Value Observed: 0.200 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Three-dimensional rational approach to the discovery of potent substituted cyclopropyl urea soluble epoxide hydrolase inhibitors.

Takai, K.Chiyo, N.Nakajima, T.Nariai, T.Ishikawa, C.Nakatani, S.Ikeno, A.Yamamoto, S.Sone, T.

(2015) Bioorg Med Chem Lett 25: 1705-1708

  • DOI: https://doi.org/10.1016/j.bmcl.2015.02.076
  • Primary Citation of Related Structures:  
    4X6X, 4X6Y

  • PubMed Abstract: 

    We have previously reported a series of cyclopropyl urea derivatives as potent orally available soluble epoxide hydrolase (sEH) inhibitors. Here, we designed and synthesized three substituted cyclopropane derivatives that occupy all available pockets of sEH catalytic domain. Compound 14 with a diphenyl substituted cyclopropyl moiety showed good sEH inhibitory activity. Co-crystal structure of this compound and human sEH hydrolase catalytic domain revealed enzyme pockets occupied by the phenoxypiperidine part and the diphenyl cyclopropyl moiety. Furthermore, investigation of the phenoxypiperidine part of compound 14 resulted in the discovery of compound 19, which showed potent sEH inhibitory activity (sub-nM sEH IC50 values).


  • Organizational Affiliation

    Drug Research Division, Sumitomo Dainippon Pharma Co., Ltd, 3-1-98 Kasugade-naka, Konohana-ku, Osaka-city, Osaka 554-0022, Japan. Electronic address: kentaro-takai@ds-pharma.co.jp.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Bifunctional epoxide hydrolase 2
A, B
336Homo sapiensMutation(s): 0 
Gene Names: EPHX2
EC: 3.3.2.10
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
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
S74
Query on S74

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
3-{4-[(1-{[(1s,2R,3S)-2,3-diphenylcyclopropyl]carbamoyl}piperidin-4-yl)oxy]phenyl}propanoic acid
C30 H32 N2 O4
VQQDJLMIDZHNMF-WLNZHLEZSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
S74 Binding MOAD:  4X6X IC50: 2.3 (nM) from 1 assay(s)
BindingDB:  4X6X IC50: 2.3 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.222 
  • R-Value Work: 0.199 
  • R-Value Observed: 0.200 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 129.406α = 90
b = 80.544β = 125.7
c = 88.253γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
HKL-2000data scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2015-04-08
    Type: Initial release
  • Version 1.1: 2015-04-15
    Changes: Database references
  • Version 1.2: 2020-02-05
    Changes: Data collection, Database references, Derived calculations, Source and taxonomy
  • Version 1.3: 2023-11-08
    Changes: Data collection, Database references, Refinement description