Format

Send to

Choose Destination
Nat Rev Drug Discov. 2013 Mar;12(3):205-16. doi: 10.1038/nrd3954. Epub 2012 Feb 15.

Signalling bias in new drug discovery: detection, quantification and therapeutic impact.

Author information

1
Department of Pharmacology, University of North Carolina School of Medicine, 120 Mason Farm Road, Room 4042, Genetic Medicine Building, CB 7365, Chapel Hill, North Carolina 2759-97365, USA. kenakin@email.unc.edu

Abstract

Agonists of seven-transmembrane receptors, also known as G protein-coupled receptors (GPCRs), do not uniformly activate all cellular signalling pathways linked to a given seven-transmembrane receptor (a phenomenon termed ligand or agonist bias); this discovery has changed how high-throughput screens are designed and how lead compounds are optimized for therapeutic activity. The ability to experimentally detect ligand bias has necessitated the development of methods for quantifying agonist bias in a way that can be used to guide structure-activity studies and the selection of drug candidates. Here, we provide a viewpoint on which methods are appropriate for quantifying bias, based on knowledge of how cellular and intracellular signalling proteins control the conformation of seven-transmembrane receptors. We also discuss possible predictions of how biased molecules may perform in vivo, and what potential therapeutic advantages they may provide.

PMID:
23411724
DOI:
10.1038/nrd3954
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Nature Publishing Group
Loading ...
Support Center