High-potency olfactory receptor agonists discovered by virtual high-throughput screening: molecular probes for receptor structure and olfactory function

Neuron. 2008 Dec 10;60(5):767-74. doi: 10.1016/j.neuron.2008.11.014.


The detection of diverse chemical structures by the vertebrate olfactory system is accomplished by the recognition of odorous ligands by their cognate receptors. In the present study, we used computational screening to discover novel high-affinity agonists of an olfactory G protein-coupled receptor that recognizes amino acid ligands. Functional testing of the top candidates validated several agonists with potencies higher than any of the receptor's known natural ligands. Computational modeling revealed molecular interactions involved in ligand binding and further highlighted interactions that have been conserved in evolutionarily divergent amino acid receptors. Significantly, the top compounds display robust activities as odorants in vivo and include a natural product that may be used to signal the presence of bacteria in the environment. Our virtual screening approach should be applicable to the identification of new bioactive molecules for probing the structure of chemosensory receptors and the function of chemosensory systems in vivo.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acids / chemistry
  • Animals
  • Calcium / metabolism
  • Cell Line, Transformed
  • Computer-Aided Design
  • Drug Evaluation, Preclinical / methods*
  • Goldfish
  • Humans
  • Ligands*
  • Models, Molecular
  • Molecular Probes
  • Olfactory Receptor Neurons / drug effects
  • Olfactory Receptor Neurons / physiology*
  • Protein Binding / drug effects
  • Protein Binding / physiology
  • Protein Conformation
  • ROC Curve
  • Receptors, Odorant / antagonists & inhibitors*
  • Receptors, Odorant / chemistry
  • Receptors, Odorant / physiology*
  • Small Molecule Libraries
  • Smell / physiology*
  • Structure-Activity Relationship


  • Amino Acids
  • Ligands
  • Molecular Probes
  • Receptors, Odorant
  • Small Molecule Libraries
  • Calcium