CCR2: characterization of the antagonist binding site from a combined receptor modeling/mutagenesis approach

J Med Chem. 2003 Sep 11;46(19):4070-86. doi: 10.1021/jm030862l.


We describe here a classical molecular modeling exercise that was carried out to provide a basis for the design of novel antagonist ligands of the CCR2 receptor. Using a theoretical model of the CCR2 receptor, docking studies were carried out to define plausible binding modes for the various known antagonist ligands, including our own series of indole piperidine compounds. On the basis of these results, a number of site-directed mutations (SDM) were designed that were intended to verify the proposed docking models. From these it was clear that further refinements would be necessary in the model. This was aided by the publication of a crystal structure of bovine rhodopsin, and a new receptor model was built by homology to this structure. This latest model enabled us to define ligand-docking hypotheses that were in complete agreement with the results of the SDM experiments.

Publication types

  • Comparative Study

MeSH terms

  • Amino Acid Substitution
  • Animals
  • Binding Sites
  • Binding, Competitive
  • CHO Cells
  • Cattle
  • Cell Line
  • Chemotaxis / drug effects
  • Cricetinae
  • Humans
  • Indoles / chemistry
  • Indoles / metabolism
  • Indoles / pharmacology
  • Kinetics
  • Models, Molecular
  • Monocytes / drug effects
  • Monocytes / physiology
  • Mutagenesis, Site-Directed
  • Piperidines / chemistry
  • Piperidines / metabolism
  • Piperidines / pharmacology
  • Radioligand Assay
  • Receptors, CCR2
  • Receptors, Chemokine / antagonists & inhibitors*
  • Receptors, Chemokine / chemistry
  • Receptors, Chemokine / genetics
  • Receptors, Chemokine / metabolism*
  • Recombinant Proteins / antagonists & inhibitors
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Rhodopsin / chemistry
  • Rhodopsin / genetics
  • Structural Homology, Protein
  • Transfection


  • CCR2 protein, human
  • Indoles
  • Piperidines
  • Receptors, CCR2
  • Receptors, Chemokine
  • Recombinant Proteins
  • Rhodopsin