Nature Reviews Drug Discovery 12, 205-216 (March 2013) | doi:10.1038/nrd3954

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

See also: Correspondence by Sudarshan Rajagopal | Reply by Terry Kenakin & Arthur Christopoulos

Terry Kenakin1 & Arthur Christopoulos2  About the authors


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.

Author affiliations

  1. Terry Kenakin is at the 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.
  2. Arthur Christopoulos is in the Drug Discovery Biology Theme and at the Department of Pharmacology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.

Correspondence to: Terry Kenakin1 Email:

Published online 15 February 2012

Additional data