3DN5

Aldose Reductase in complex with novel biarylic inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.45 Å
  • R-Value Free: 0.200 
  • R-Value Work: 0.128 
  • R-Value Observed: 0.131 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Structure-Based Optimization of Aldose Reductase Inhibitors Originating from Virtual Screening

Eisenmann, M.Steuber, H.Zentgraf, M.Altenkamper, M.Ortmann, R.Perruchon, J.Klebe, G.Schlitzer, M.

(2009) ChemMedChem 4: 809-819

  • DOI: https://doi.org/10.1002/cmdc.200800410
  • Primary Citation of Related Structures:  
    3DN5

  • PubMed Abstract: 

    Diabetes mellitus is a universal health problem. The World Health Organization (WHO) estimates that 150 million people suffer from diabetes mellitus worldwide in 2005. Long-term complications are a serious problem in the treatment of diabetes, manifesting in macrovascular and microvascular complications. Sorbitol accumulation has been proposed to be an important factor in the development of microvascular complications such as nephropathy, neuropathy, retinopathy or cataract. Catalyzing the NADPH-dependent reduction of glucose to sorbitol, aldose reductase (ALR2) is an important target in the prevention of these complications. The development of novel aldose reductase inhibitors is expected to benefit strongly from a structure-based design approach. A virtual screening based on the ultrahigh-resolution crystal structure of the inhibitor IDD 594 in complex with human ALR2 identified two compounds with IC(50) values in the low micro- to submicromolar range. Based on the known interactions between the ligands and their binding pocket, we simplified the lead structures to give the minimal structural requirements and developed synthetic pathways from commercially available compounds. The newly synthesized compounds were assayed for their inhibition of ALR2, showing inhibitory activities down to the nanomolar range. Crystal structure analysis of the most potent derivative of our series revealed insights into the binding mode of the inhibitors.


  • Organizational Affiliation

    Institut für Pharmazeutische Chemie, Philipps Universität Marburg, Marbacher Weg 6, 35032 Marburg, Germany.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Aldose reductase316Homo sapiensMutation(s): 0 
Gene Names: alr2
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
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
NAP
Query on NAP

Download Ideal Coordinates CCD File 
B [auth A]NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE
C21 H28 N7 O17 P3
XJLXINKUBYWONI-NNYOXOHSSA-N
53N
Query on 53N

Download Ideal Coordinates CCD File 
C [auth A]3-[5-(3-nitrophenyl)thiophen-2-yl]propanoic acid
C13 H11 N O4 S
IHKCOKRMJRDWAL-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
53N Binding MOAD:  3DN5 IC50: 170 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.45 Å
  • R-Value Free: 0.200 
  • R-Value Work: 0.128 
  • R-Value Observed: 0.131 
  • Space Group: P 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 40.29α = 75.85
b = 47.155β = 67.48
c = 47.33γ = 76.59
Software Package:
Software NamePurpose
CrystalCleardata collection
CNSrefinement
SHELXL-97refinement
HKL-2000data reduction
HKL-2000data scaling
CNSphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2009-04-07
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2023-11-01
    Changes: Data collection, Database references, Derived calculations, Refinement description