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

Sean Michael Boyle,Anandasankar Ray,Shane Mcinally

doi:10.7554/elife.01120

Abstract

Coding of information in the peripheral olfactory system depends on two fundamental : 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. DOI:http://dx.doi.org/10.7554/eLife.01120.001.

Highlights

The peripheral olfactory system is unparalleled in its ability to detect and discriminate amongst an extremely large number of volatile compounds in the environment
There are two major rate-limiting steps in analysis of peripheral coding in olfaction: a very small proportion of chemical space can be systematically tested for its activity on odorant receptors and a very small fraction of the numerous odorant receptors have been tested for responses (Araneda et al, 2000; Hallem et al, 2004; Hallem and Carlson, 2006; Pelz et al, 2006; Kreher et al, 2008; Saito et al, 2009; Mathew et al, 2013)
We report an in silico approach to systematically identify ligands from a vast chemical space for a large number of Odorant receptors (Ors) expressed in the antenna of Drosophila

Summary

Introduction

The peripheral olfactory system is unparalleled in its ability to detect and discriminate amongst an extremely large number of volatile compounds in the environment. Each volatile chemical in the environment is thought to interact with a specific subset of odorant receptors depending upon odor structure and binding sites on the receptor This precise detection and coding of odors by the peripheral olfactory neurons are subsequently processed, transformed and integrated in the central nervous system to generate specific behavioral responses that are critical for survival such as finding food, finding mates, avoiding predators etc (van der Goes van Naters and Carlson, 2006). There are two major rate-limiting steps in analysis of peripheral coding in olfaction: a very small proportion of chemical space can be systematically tested for its activity on odorant receptors and a very small fraction of the numerous odorant receptors have been tested for responses (Araneda et al, 2000; Hallem et al, 2004; Hallem and Carlson, 2006; Pelz et al, 2006; Kreher et al, 2008; Saito et al, 2009; Mathew et al, 2013).

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