Agonists of G-Protein-Coupled Odorant Receptors Are Predicted from Chemical Features.
Published
Journal Article
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.
Full Text
Duke Authors
Cited Authors
- Bushdid, C; de March, CA; Fiorucci, S; Matsunami, H; Golebiowski, J
Published Date
- May 3, 2018
Published In
Volume / Issue
- 9 / 9
Start / End Page
- 2235 - 2240
PubMed ID
- 29648835
Pubmed Central ID
- 29648835
Electronic International Standard Serial Number (EISSN)
- 1948-7185
Digital Object Identifier (DOI)
- 10.1021/acs.jpclett.8b00633
Language
- eng
Conference Location
- United States