Exploring use of unsupervised clustering to associate signaling profiles of GPCR ligands to clinical response
Nat Commun. 2019 Sep 9;10(1):4075. doi: 10.1038/s41467-019-11875-6.
Besma Benredjem 1 2, Jonathan Gallion 3, Dennis Pelletier 4, Paul Dallaire 1 2, Johanie Charbonneau 2, Darren Cawkill 4 5, Karim Nagi 6, Mark Gosink 4, Viktoryia Lukasheva 7, Stephen Jenkinson 4 8, Yong Ren 4 9, Christopher Somps 4, Brigitte Murat 7, Emma Van Der Westhuizen 7 10, Christian Le Gouill 7, Olivier Lichtarge 3, Anne Schmidt 4, Michel Bouvier 11, Graciela Pineyro 12 13
PMID: 31501422 PMCID: PMC6733853 DOI: 10.1038/s41467-019-11875-6
Signaling diversity of G protein-coupled (GPCR) ligands provides novel opportunities to develop more effective, better-tolerated therapeutics. Taking advantage of these opportunities requires identifying which effectors should be specifically activated or avoided so as to promote desired clinical responses and avoid side effects. However, identifying signaling profiles that support desired clinical outcomes remains challenging. This study describes signaling diversity of mu opioid receptor (MOR) ligands in terms of logistic and operational parameters for ten different in vitro readouts. It then uses unsupervised clustering of curve parameters to: classify MOR ligands according to similarities in type and magnitude of response, associate resulting ligand categories with frequency of undesired events reported to the pharmacovigilance program of the Food and Drug Administration and associate signals to side effects. The ability of the classification method to associate specific in vitro signaling profiles to clinically relevant responses was corroborated using β2-adrenergic receptor ligands.