title: High-potency olfactory receptor agonists discovered by virtual high-throughput screening: molecular probes for receptor structure and olfactory function.
abstract: 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.
authors.affiliation: Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques, CNRS UMR-8601, Université Paris Descartes, 45 rue des Saints Pères, 75270 Paris Cedex 06, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Triballeau
authors.forename: Eric
authors.initials: E
authors.lastname: Van Name
authors.forename: Guillaume
authors.initials: G
authors.lastname: Laslier
authors.forename: Diana
authors.initials: D
authors.lastname: Cai
authors.forename: Guillaume
authors.initials: G
authors.lastname: Paillard
authors.forename: Peter W
authors.initials: PW
authors.lastname: Sorensen
authors.forename: Rémy
authors.initials: R
authors.lastname: Hoffmann
authors.forename: Hugues-Olivier
authors.initials: HO
authors.lastname: Bertrand
authors.forename: John
authors.initials: J
authors.lastname: Ngai
authors.forename: Francine C
authors.initials: FC
authors.lastname: Acher
mesh_terms: D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002461:Cell Line, Transformed; D017076:Computer-Aided Design; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D006054:Goldfish; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015335:Molecular Probes; D018034:Olfactory Receptor Neurons / Q000187:drug effects / Q000502:physiology*; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D011487:Protein Conformation; D012372:ROC Curve; D018035:Receptors, Odorant / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000502:physiology*; D054852:Small Molecule Libraries; D012903:Smell / Q000502:physiology*; D013329:Structure-Activity Relationship
chemical_list: D000596:Amino Acids; D008024:Ligands; D015335:Molecular Probes; D018035:Receptors, Odorant; D054852:Small Molecule Libraries; D002118:Calcium