title: Signaling bias in drug discovery.
abstract: The availability of different functional pharmacological assays has revealed that agonists for receptors that are pleiotropically coupled to multiple signaling pathways in the cell can emphasize signals to some pathways over others, i.e. can be biased toward certain signals. This, in turn, opens the possibility that molecules can be made to emphasize favorable signals, de-emphasize harmful signals or selectively block the ability of the natural agonist to produce unfavorable signals. Areas covered: This paper discusses the mechanism of biased signaling, the possible therapeutic implications of this effect, methods to quantify and measure bias and the current literature describing the translation of biased measure in vitro to in vivo systems. In addition, the challenges of exploiting this mechanism for therapy are outlined. Expert opinion: While this mechanism is well established and ubiquitous in pharmacology and easily measured in vitro, there are theoretical and practical hurdles to overcome to the fruitful utilization of signaling bias in therapeutic systems. There will be failures in the translation of biased molecules in vivo because of these challenges but hopefully also success and these latter translations hopefully will provide guidance in exploiting this effect further for therapy.
authors.affiliation: a Department of Pharmacology , University of North Carolina School of Medicine , Chapel Hill , NC , USA.
authors.forename: Terry
authors.initials: T
authors.lastname: Kenakin
mesh_terms: D000818:Animals; D015195:Drug Design; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D043562:Receptors, G-Protein-Coupled
keywords: ((Allosteric) OR allosterisms) OR allostery; biased signaling; drug discovery; receptors