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PDBsum entry 1kwq

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protein ligands metals links
Lyase PDB id
1kwq
Jmol
Contents
Protein chain
258 a.a. *
Ligands
SG1
Metals
_ZN
_HG
Waters ×111
* Residue conservation analysis
PDB id:
1kwq
Name: Lyase
Title: Human carbonic anhydrase ii complexed with inhibitor 2000-07
Structure: Carbonic anhydrase ii. Chain: a. Synonym: carbonate dehydratase ii, ca-ii. Ec: 4.2.1.1
Source: Homo sapiens. Human. Organism_taxid: 9606
Resolution:
2.60Å     R-factor:   0.194     R-free:   0.283
Authors: S.Grueneberg,M.T.Stubbs
Key ref: S.Grüneberg et al. (2002). Successful virtual screening for novel inhibitors of human carbonic anhydrase: strategy and experimental confirmation. J Med Chem, 45, 3588-3602. PubMed id: 12166932 DOI: 10.1021/jm011112j
Date:
30-Jan-02     Release date:   07-Jan-03    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P00918  (CAH2_HUMAN) -  Carbonic anhydrase 2
Seq:
Struc:
260 a.a.
258 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.4.2.1.1  - Carbonate dehydratase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: H2CO3 = CO2 + H2O
H(2)CO(3)
= CO(2)
+ H(2)O
      Cofactor: Zn(2+)
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular space   11 terms 
  Biological process     angiotensin-mediated signaling pathway   21 terms 
  Biochemical function     protein binding     5 terms  

 

 
    Added reference    
 
 
DOI no: 10.1021/jm011112j J Med Chem 45:3588-3602 (2002)
PubMed id: 12166932  
 
 
Successful virtual screening for novel inhibitors of human carbonic anhydrase: strategy and experimental confirmation.
S.Grüneberg, M.T.Stubbs, G.Klebe.
 
  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.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21524585 Z.Xiao, R.Duan, W.Cui, Y.Zhang, S.Zhang, F.Chen, Y.Zhang, J.Liu, D.Zhang, Y.Meng, L.Wang, and H.Wang (2011).
Synthesis and evaluation of new carbonic anhydrase inhibitors.
  Bioorg Med Chem, 19, 3221-3228.  
19908272 D.M.Krüger, and A.Evers (2010).
Comparison of structure- and ligand-based virtual screening protocols considering hit list complementarity and enrichment factors.
  ChemMedChem, 5, 148-158.  
19063592 A.Amadasi, A.Mozzarelli, C.Meda, A.Maggi, and P.Cozzini (2009).
Identification of xenoestrogens in food additives by an integrated in silico and in vitro approach.
  Chem Res Toxicol, 22, 52-63.  
19433475 C.M.Song, S.J.Lim, and J.C.Tong (2009).
Recent advances in computer-aided drug design.
  Brief Bioinform, 10, 579-591.  
19235177 M.I.Zavodszky, A.Rohatgi, J.R.Van Voorst, H.Yan, and L.A.Kuhn (2009).
Scoring ligand similarity in structure-based virtual screening.
  J Mol Recognit, 22, 280-292.  
18172702 A.Beautrait, V.Leroux, M.Chavent, L.Ghemtio, M.D.Devignes, M.Smaïl-Tabbone, W.Cai, X.Shao, G.Moreau, P.Bladon, J.Yao, and B.Maigret (2008).
Multiple-step virtual screening using VSM-G: overview and validation of fast geometrical matching enrichment.
  J Mol Model, 14, 135-148.  
18161740 K.D'Ambrosio, B.Masereel, A.Thiry, A.Scozzafava, C.T.Supuran, and G.De Simone (2008).
Carbonic anhydrase inhibitors: binding of indanesulfonamides to the human isoform II.
  ChemMedChem, 3, 473-477.
PDB codes: 2qo8 2qoa
18037921 P.Taylor, E.Blackburn, Y.G.Sheng, S.Harding, K.Y.Hsin, D.Kan, S.Shave, and M.D.Walkinshaw (2008).
Ligand discovery and virtual screening using the program LIDAEUS.
  Br J Pharmacol, 153, S55-S67.  
18335973 V.M.Krishnamurthy, G.K.Kaufman, A.R.Urbach, I.Gitlin, K.L.Gudiksen, D.B.Weibel, and G.M.Whitesides (2008).
Carbonic anhydrase as a model for biophysical and physical-organic studies of proteins and protein-ligand binding.
  Chem Rev, 108, 946.  
17257425 C.Konstantinou-Kirtay, J.B.Mitchell, and J.A.Lumley (2007).
Scoring functions and enrichment: a case study on Hsp90.
  BMC Bioinformatics, 8, 27.  
17665409 G.E.Höst, J.Razkin, L.Baltzer, and B.H.Jonsson (2007).
Combined enzyme and substrate design: grafting of a cooperative two-histidine catalytic motif into a protein targeted at the scissile bond in a designed ester substrate.
  Chembiochem, 8, 1570-1576.  
17393392 P.Block, N.Weskamp, A.Wolf, and G.Klebe (2007).
Strategies to search and design stabilizers of protein-protein interactions: a feasibility study.
  Proteins, 68, 170-186.  
16902938 A.Hillebrecht, C.T.Supuran, and G.Klebe (2006).
Integrated approach using protein and ligand information to analyze selectivity- and affinity-determining features of carbonic anhydrase isozymes.
  ChemMedChem, 1, 839-853.  
16793526 G.Klebe (2006).
Virtual ligand screening: strategies, perspectives and limitations.
  Drug Discov Today, 11, 580-594.  
16231201 C.Machicado, J.López-Llano, S.Cuesta-López, M.Bueno, and J.Sancho (2005).
Design of ligand binding to an engineered protein cavity using virtual screening and thermal up-shift evaluation.
  J Comput Aided Mol Des, 19, 421-443.  
15959566 G.R.Desiraju (2005).
C-H...O and other weak hydrogen bonds. From crystal engineering to virtual screening.
  Chem Commun (Camb), (), 2995-3001.  
15526325 M.Kontoyianni, G.S.Sokol, and L.M.McClellan (2005).
Evaluation of library ranking efficacy in virtual screening.
  J Comput Chem, 26, 11-22.  
16028223 S.Cotesta, F.Giordanetto, J.Y.Trosset, P.Crivori, R.T.Kroemer, P.F.Stouten, and A.Vulpetti (2005).
Virtual screening to enrich a compound collection with CDK2 inhibitors using docking, scoring, and composite scoring models.
  Proteins, 60, 629-643.  
15602552 B.K.Shoichet (2004).
Virtual screening of chemical libraries.
  Nature, 432, 862-865.  
15288244 J.M.Jansen, and E.J.Martin (2004).
Target-biased scoring approaches and expert systems in structure-based virtual screening.
  Curr Opin Chem Biol, 8, 359-364.  
14597633 M.Hrmova, R.De Gori, B.J.Smith, A.Vasella, J.N.Varghese, and G.B.Fincher (2004).
Three-dimensional structure of the barley beta-D-glucan glucohydrolase in complex with a transition state mimic.
  J Biol Chem, 279, 4970-4980.
PDB code: 1lq2
15146480 O.Kraemer, I.Hazemann, A.D.Podjarny, and G.Klebe (2004).
Virtual screening for inhibitors of human aldose reductase.
  Proteins, 55, 814-823.  
15288243 T.I.Oprea, and H.Matter (2004).
Integrating virtual screening in lead discovery.
  Curr Opin Chem Biol, 8, 349-358.  
12415248 J.Bajorath (2002).
Integration of virtual and high-throughput screening.
  Nat Rev Drug Discov, 1, 882-894.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.