1EF3

FIDARESTAT BOUND TO HUMAN ALDOSE REDUCTASE


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.80 Å
  • R-Value Free: 0.278 
  • R-Value Work: 0.186 
  • R-Value Observed: 0.191 

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Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

A potent aldose reductase inhibitor, (2S,4S)-6-fluoro-2', 5'-dioxospiro[chroman-4,4'-imidazolidine]-2-carboxamide (Fidarestat): its absolute configuration and interactions with the aldose reductase by X-ray crystallography.

Oka, M.Matsumoto, Y.Sugiyama, S.Tsuruta, N.Matsushima, M.

(2000) J Med Chem 43: 2479-2483

  • DOI: https://doi.org/10.1021/jm990502r
  • Primary Citation of Related Structures:  
    1EF3

  • PubMed Abstract: 

    The absolute configuration of the aldose reductase (AR) inhibitor, (+)-(2S,4S)-6-fluoro-2',5'-dioxospiro¿chroman-4, 4'-imidazolidine-2-carboxamide (fidarestat), was established indirectly by single-crystal X-ray analysis of (+)-(2S, 4S)-8-bromo-6-fluoro-2',5'-dioxospiro¿chroman-4, 4'-imidazolidine-2-carboxylic acid (1). The crystal structure of human AR complexed with fidarestat was determined, and the specific inhibition activity was discussed on the basis of the three-dimensional interactions between them. The structure clarified that fidarestat was located in the active site by hydrophilic and hydrophobic interactions and that the carbamoyl group of fidarestat was a very effective substituent for affinity to AR and for selectivity between AR and aldehyde reductase (AHR). Explanations for the differences between the observed activities of fidarestat and its stereoisomer 2 were suggested by computer modeling.


  • Organizational Affiliation

    Rational Drug Design Laboratories, 4-1-1, Misato, Matsukawa-machi, Fukushima 960-1242, Japan. m_oka@mb6.skk-net.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
ALDOSE REDUCTASE
A, B
315Homo sapiensMutation(s): 0 
EC: 1.1.1.21
UniProt & NIH Common Fund Data Resources
Find proteins for P15121 (Homo sapiens)
Explore P15121 
Go to UniProtKB:  P15121
PHAROS:  P15121
GTEx:  ENSG00000085662 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP15121
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
FID BindingDB:  1EF3 Kd: 16 (nM) from 1 assay(s)
IC50: min: 9, max: 35 (nM) from 5 assay(s)
-TΔS: min: -9.80e+0, max: 29.71 (kJ/mol) from 6 assay(s)
ΔH: min: -3.54e+1, max: -2.99e+1 (kJ/mol) from 2 assay(s)
ΔG: min: -4.67e+1, max: -2.93e+1 (kJ/mol) from 8 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.80 Å
  • R-Value Free: 0.278 
  • R-Value Work: 0.186 
  • R-Value Observed: 0.191 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 96.14α = 90
b = 62.56β = 101.6
c = 118.99γ = 90
Software Package:
Software NamePurpose
X-PLORmodel building
X-PLORrefinement
DENZOdata reduction
SCALEPACKdata scaling
X-PLORphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2001-02-07
    Type: Initial release
  • Version 1.1: 2008-04-27
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2018-01-31
    Changes: Experimental preparation
  • Version 1.4: 2023-08-09
    Changes: Data collection, Database references, Derived calculations, Refinement description