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PMID: 23411724 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Review

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

Nature reviews. Drug discovery ·Vol. 12 ·No. 3 ·2013-03-00 ·Pages 205-16

Kenakin T, Christopoulos A

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.

MeSH Terms
Algorithms Animals Drug Discovery Drug Therapy Humans Ligands Receptors, G-Protein-Coupled/drug effects,physiology Signal Transduction/drug effects,physiology
Chemicals
Ligands Receptors, G-Protein-Coupled
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Kenakin Terry
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
Christopoulos Arthur
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Article Info
Journal
Nature reviews. Drug discovery
Abbr.
Nat Rev Drug Discov
ISSN
1474-1784
DOI
10.1038/nrd3954
Email
kenakin@email.unc.edu
Published
2013-03-00
Epub
2012-00-15
Pages
205-16
Language
English
Region
England
NLM ID
101124171
Subset
IM
Corrections
CommentIn
PMID: 23681003
CommentIn
PMID: 23681006
CommentIn
PMID: 25323926
External Links
PubMed source DOI: 10.1038/nrd3954 View journal details
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