Reviewer #1 (Public review): Machine Learning Based Modelling of Human and Insect Olfaction Screens Millions of compounds to Identify Pleasant Smelling Insect Repellents

The rational discovery of behaviorally active odorants is impeded by limited information on how the olfactory system generates percept or valence for a volatile chemical. In previous studies, we showed that chemical informatics could be used to predict ligands for a large repertoire of odorant receptors in Drosophila (). However, it remained difficult to predict behavioral valence of volatiles since the activities of a large ensembles of odor receptors encode odor information, and little is known about the complex information processing circuitry. This is a systems-level challenge well-suited for Machine-learning approaches which we have used to model olfaction in two organisms with completely unrelated olfactory receptor proteins: humans (∼400 GPCRs) and insects (∼100 ion-channels). We use chemical structure-based Machine Learning models for prediction of valence in insects and for 146 human odor characters. Using these predictive models, we evaluate a vast chemical space of >10 million compounds in silico. Validations of human and insect behaviors yield very high success rates. The discovery of desirable fragrances for humans that are highly repulsive to insects offers a powerful integrated approach to discover new insect repellents.