High-Potency Olfactory Receptor Agonists Discovered by Virtual High-Throughput Screening: Molecular Probes for Receptor Structure and Olfactory Function
| Autor: | Guillaume Paillard, John Ngai, Rémy Hoffmann, Diana Cai, Guillaume Laslier, Eric Van Name, Peter W. Sorensen, Hugues-Olivier Bertrand, Francine Acher, Nicolas Triballeau |
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| Jazyk: | angličtina |
| Předmět: |
Models
Molecular Olfactory system Protein Conformation Neuroscience(all) Drug Evaluation Preclinical Biology Ligands Receptors Odorant 01 natural sciences Olfactory Receptor Neurons Article MOLNEURO Small Molecule Libraries Structure-Activity Relationship 03 medical and health sciences Goldfish medicine Animals Humans Structure–activity relationship Amino Acids Receptor Cell Line Transformed 030304 developmental biology 0303 health sciences Virtual screening Olfactory receptor 010405 organic chemistry General Neuroscience 0104 chemical sciences Smell medicine.anatomical_structure CHEMBIO ROC Curve Biochemistry Molecular Probes Computer-Aided Design Calcium CELLBIO Molecular probe Function (biology) Protein Binding |
| Zdroj: | Neuron. (5):767-774 |
| ISSN: | 0896-6273 |
| DOI: | 10.1016/j.neuron.2008.11.014 |
| Popis: | The detection and discrimination 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 a computational high-throughput screening strategy to discover novel high affinity agonists of an olfactory G protein-coupled receptor tuned to recognize 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 recognition by this receptor, 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 aquatic 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. |
| Databáze: | OpenAIRE |
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