Construction and validation of a RET TK catalytic domain by homology modeling

J Chem Inf Model. 2007 Mar-Apr;47(2):644-55. doi: 10.1021/ci6004383. Epub 2007 Feb 13.


RET tyrosine kinase (TK) oncoproteins are potential targets for anticancer therapy. However, the search for novel RET inhibitors has been hampered by the lack of a 3D structure of the receptor. In this study, the "open" and the "closed" structure of the RET TK catalytic domain have been built by homology modeling techniques. The structures were validated by extensive docking studies with practically all the inhibitors reported in the literature and through molecular dynamics simulations of the resulting complexes. All the expected major interactions between the active domain amino acids and the inhibitors have been reproduced in their details. Furthermore, the proposed 3D models are in agreement with the results of available mutation studies. Therefore, these models could be profitably used to filter off from large libraries new potential hit compounds able to target this enzyme.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Binding Sites
  • Catalytic Domain*
  • Computational Biology
  • Computer Simulation
  • Conserved Sequence
  • Crystallography, X-Ray
  • Databases, Protein
  • Ligands
  • Models, Biological*
  • Molecular Sequence Data
  • Mutation / genetics
  • Protein Binding
  • Protein Kinase Inhibitors / chemistry
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Protein-Tyrosine Kinases / chemistry*
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism*
  • Reproducibility of Results
  • Sequence Alignment
  • Structural Homology, Protein*


  • Ligands
  • Protein Kinase Inhibitors
  • Protein-Tyrosine Kinases