PT  - JOURNAL ARTICLE
AU  - Terry Kenakin
TI  - The Effective Application of Biased Signaling to New Drug Discovery
AID  - 10.1124/mol.115.099770
DP  - 2015 Dec 01
TA  - Molecular Pharmacology
PG  - 1055--1061
VI  - 88
IP  - 6
4099  - http://molpharm.aspetjournals.org/content/88/6/1055.short
4100  - http://molpharm.aspetjournals.org/content/88/6/1055.full
SO  - Mol Pharmacol2015 Dec 01; 88
AB  - The ability of agonists to selectively activate some but not all signaling pathways linked to pleiotropically signaling receptors has opened the possibility of obtaining molecules that emphasize beneficial signals, de-emphasize harmful signals, and concomitantly deemphasize harmful signals while blocking the harmful signals produced by endogenous agonists. The detection and quantification of biased effects is straightforward, but two important factors should be considered in the evaluation of biased effects in drug discovery. The first is that efficacy, and not bias, determines whether a given agonist signal will be observed; bias only dictates the relative concentrations at which agonist signals will appear when they do appear. Therefore, a Cartesian coordinate system plotting relative efficacy (on a scale of Log relative Intrinsic Activities) as the ordinates and Log(bias) as the abscissae is proposed as a useful tool in evaluating possible biased molecules for progression in discovery programs. Second, it should be considered that the current scales quantifying bias limit this property to the allosteric vector (ligand/receptor/coupling protein complex) and that whole-cell processing of this signal can completely change measured bias from in vitro predictions.