Expanding the olfactory code by in silico decoding of odor-receptor chemical space

Abstract

Coding of information in the peripheral olfactory system depends on two fundamental factors: interaction of individual odors with subsets of the odorant receptor repertoire and mode of signaling that an individual receptor-odor interaction elicits, activation or inhibition. We develop a cheminformatics pipeline that predicts receptor–odorant interactions from a large collection of chemical structures (>240,000) for receptors that have been tested to a smaller panel of odorants (∼100). Using a computational approach, we first identify shared structural features from known ligands of individual receptors. We then use these features to screen in silico new candidate ligands from >240,000 potential volatiles for several Odorant receptors (Ors) in the Drosophila antenna. Functional experiments from 9 Ors support a high success rate (∼71%) for the screen, resulting in identification of numerous new activators and inhibitors. Such computational prediction of receptor–odor interactions has the potential to enable systems level analysis of olfactory receptor repertoires in organisms.Although our sense of smell is regarded as inferior to that of many other species, we can nevertheless distinguish between roughly 10,000 different odors. These are made up of molecules called odorants, each of which activates a specific subset of odorant receptors in the nose. However, much of what we know about this process has come from studying the fruit fly, Drosophila, which detects odors using receptors located mainly on its antennae.The number of potential odorants in nature is vast, and only a tiny fraction of the interactions between odorants and receptors can be physically tested. To address this challenge, Boyle et al. have used a computational approach to study in depth the interactions between a subset of 24 odorant receptors in Drosophila antennae and 109 odorants.After developing a method to identify structural features shared by the odorants that activate each receptor, Boyle et al. used this information to perform a computational (in silico) screen of more than 240,000 different odorant-like volatile compounds. For each receptor, they compiled a list of the 500 odorants predicted to interact most strongly with it. They then tested their predictions for a subset of the receptors by performing experiments in living flies, and found that roughly 71% of predicted compounds did indeed activate or inhibit their receptors, compared to only 10% of a control sample.In addition to providing new insights into the nature of the interactions between odorants and their receptors, the computational screen devised by Boyle et al. could aid the development of novel insect repellents, or compounds that mask the odors used by disease-causing insects to identify their hosts. It could also be used in the future to develop novel flavors and fragrances.