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Agonists of G-Protein-Coupled Odorant Receptors Are Predicted from Chemical Features

Title
Agonists of G-Protein-Coupled Odorant Receptors Are Predicted from Chemical Features
Authors
Bushdid, C.De March, C.A.Fiorucci, S.Matsunami, H.Golebiowski, Jerome
Issue Date
2018-05
Citation
Journal of Physical Chemistry Letters, 9(9), 2235-2240
Type
Article
Article Type
Article
Keywords
Artificial intelligenceIndicators (chemical)Learning systemsLigandsProteinsChemical descriptorsChemical featuresG protein coupled receptorsIn-vitro assaysOdorant receptorsOlfactory functionsSupport vector machine algorithmSystematic controlOdors
ISSN
1948-7185
Abstract
Predicting the activity of chemicals for a given odorant receptor is a longstanding challenge. Here the activity of 258 chemicals on the human G-protein-coupled odorant receptor (OR)51E1, also known as prostate-specific G-protein-coupled receptor 2 (PSGR2), was virtually screened by machine learning using 4884 chemical descriptors as input. A systematic control by functional in vitro assays revealed that a support vector machine algorithm accurately predicted the activity of a screened library. It allowed us to identify two novel agonists in vitro for OR51E1. The transferability of the protocol was assessed on OR1A1, OR2W1, and MOR256-3 odorant receptors, and, in each case, novel agonists were identified with a hit rate of 39-50%. We further show how ligands' efficacy is encoded into residues within OR51E1 cavity using a molecular modeling protocol. Our approach allows widening the chemical spaces associated with odorant receptors. This machine-learning protocol based on chemical features thus represents an efficient tool for screening ligands for G-protein-coupled odorant receptors that modulate non-olfactory functions or, upon combinatorial activation, give rise to our sense of smell. © 2018 American Chemical Society.
URI
http://hdl.handle.net/20.500.11750/6418
DOI
10.1021/acs.jpclett.8b00633
Publisher
American Chemical Society
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