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.
Bibliographical noteFunding Information:
This study was supported by grants from the National Institute on Deafness and Other Communication Disorders (J.N.), and the Fédération pour la Recherche sur le Cerveau, the Agence Nationale pour la Recherche, and the Fondation de France Comité Parkinson (F.C.A.). N.T. was the recipient of a CIFRE grant (ref. 738/2002) provided by the Association Nationale pour la Recherche Technique and Accelrys. D.C. was an LSSURP participant supported by an IGERT grant from the NSF (NSF DGE-0653827). We thank Maria Waldhoer and Jennifer Whistler for their invaluable and generous assistance with the Flexstation assays, Haude Levesque for assistance with the EOG recordings, and Delphine Rigault for technical support with the commercial hits.