1KWQ

HUMAN CARBONIC ANHYDRASE II COMPLEXED WITH INHIBITOR 2000-07


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.60 Å
  • R-Value Free: 0.283 
  • R-Value Work: 0.194 

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Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Successful virtual screening for novel inhibitors of human carbonic anhydrase: strategy and experimental confirmation.

Gruneberg, S.Stubbs, M.T.Klebe, G.

(2002) J Med Chem 45: 3588-3602

  • DOI: https://doi.org/10.1021/jm011112j
  • Primary Citation of Related Structures:  
    1KWQ, 1KWR

  • PubMed Abstract: 

    Virtual screening of compound libraries is an alternative and complementary approach to high-throughput screening in the lead discovery process. A new strategy is described to search for possible leads of human carbonic anhydrase II, applying a protocol of several consecutive hierarchical filters involving a preselection based on functional group requirements and fast pharmacophore matching. A suitable pharmacophore is derived by a sophisticated "hot spot" analysis of the binding site to detect regions favorable for protein-ligand interactions. In subsequent steps, molecular similarity with known reference ligands is used to rerank the hits from the pharmacophore matching. Finally the best scored candidates are docked flexibly into the protein binding pocket. After examination of the affinity predictions, 13 compounds were selected for experimental testing. Of these 13, three could be shown to be subnanomolar, one is nanomolar, while a further seven are micromolar inhibitors. The binding mode of two hits could be confirmed by crystal structure analysis. The novelty of the discovered leads is best supported by the fact that a search in the patent literature showed the newly discovered subnanomolar compounds to comprise scaffolds not yet covered by existing patents.


  • Organizational Affiliation

    Institute of Pharmaceutical Chemistry, University of Marburg, Marbacher Weg 6, D-35032 Marburg, Germany.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Carbonic anhydrase II260Homo sapiensMutation(s): 0 
EC: 4.2.1.1
UniProt & NIH Common Fund Data Resources
Find proteins for P00918 (Homo sapiens)
Explore P00918 
Go to UniProtKB:  P00918
PHAROS:  P00918
GTEx:  ENSG00000104267 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP00918
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
SG1 PDBBind:  1KWQ IC50: 0.62 (nM) from 1 assay(s)
BindingDB:  1KWQ IC50: 0.62 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.60 Å
  • R-Value Free: 0.283 
  • R-Value Work: 0.194 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 42.69α = 90
b = 41.69β = 104.78
c = 72.64γ = 90
Software Package:
Software NamePurpose
SCALEPACKdata scaling
X-PLORmodel building
X-PLORrefinement
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: 2003-01-07
    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: 2017-10-11
    Changes: Advisory, Refinement description
  • Version 1.4: 2024-02-14
    Changes: Advisory, Data collection, Database references, Derived calculations