Identification of nonpeptide CCR5 receptor agonists by structure-based virtual screening

J Med Chem. 2007 Mar 22;50(6):1294-303. doi: 10.1021/jm061389p. Epub 2007 Feb 21.


A three-dimensional model of the chemokine receptor CCR5 has been built to fulfill structural peculiarities of its alpha-helix bundle and to distinguish known CCR5 antagonists from randomly chosen drug-like decoys. In silico screening of a library of 1.6 million commercially available compounds against the CCR5 model by sequential filters (drug-likeness, 2-D pharmacophore, 3-D docking, scaffold clustering) yielded a hit list of 59 compounds, out of which 10 exhibited a detectable binding affinity to the CCR5 receptor. Unexpectedly, most binders tested in a functional assay were shown to be agonists of the CCR5 receptor. A follow-up database query based on similarity to the most potent binders identified three new CCR5 agonists. Despite a moderate affinity of all nonpeptide ligands for the CCR5 receptor, one of the agonists was shown to promote efficient receptor internalization, which is a process therapeutically favorable for protection against HIV-1 infection.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • CCR5 Receptor Antagonists
  • Models, Molecular*
  • Molecular Sequence Data
  • Molecular Structure
  • Piperazines / chemistry
  • Piperidines / chemistry
  • Protein Structure, Tertiary
  • Pyridazines / chemistry
  • Pyrrolidines / chemistry
  • Quantitative Structure-Activity Relationship*
  • Quinazolines / chemistry
  • Receptors, CCR5 / agonists*
  • Receptors, CCR5 / chemistry*
  • Sequence Homology, Amino Acid
  • Triazoles / chemistry


  • CCR5 Receptor Antagonists
  • Piperazines
  • Piperidines
  • Pyridazines
  • Pyrrolidines
  • Quinazolines
  • Receptors, CCR5
  • Triazoles