Computational modeling of the olfactory receptor Olfr73 suggests a molecular basis for low potency of olfactory receptor-activating compounds.
The mammalian olfactory system uses hundreds of specialized G-protein-coupled olfactory receptors (ORs) to discriminate a nearly unlimited number of odorants. Cognate agonists of most ORs have not yet been identified and potential non-olfactory processes mediated by ORs are unknown. Here, we used molecular modeling, fingerprint interaction analysis and molecular dynamics simulations to show that the binding pocket of the prototypical olfactory receptor Olfr73 is smaller, but more flexible, than binding pockets of typical non-olfactory G-protein-coupled receptors. We extended our modeling to virtual screening of a library of 1.6 million compounds against Olfr73. Our screen predicted 25 Olfr73 agonists beyond traditional odorants, of which 17 compounds, some with therapeutic potential, were validated in cell-based assays. Our modeling suggests a molecular basis for reduced interaction contacts between an odorant and its OR and thus the typical low potency of OR-activating compounds. These results provide a proof-of-principle for identifying novel therapeutic OR agonists.
['Yuan|Shuguang|S|0000-0001-9858-4742', 'Dahoun|Thamani|T|', 'Brugarolas|Marc|M|', 'Pick|Horst|H|', 'Filipek|Slawomir|S|', 'Vogel|Horst|H|']
D000818:Animals D020650:Combinatorial Chemistry Techniques D004353:Drug Evaluation, Preclinical D051379:Mice D008840:Microfilament Proteins D008958:Models, Molecular D056004:Molecular Dynamics Simulation D009812:Odorants D011485:Protein Binding D011487:Protein Conformation D018035:Receptors, Odorant D054852:Small Molecule Libraries D013329:Structure-Activity Relationship
Computational biophysics Drug screening Protein function predictions Virtual drug screening