Biased ligand quantification in drug discovery: from theory to high throughput screening to identify new biased μ opioid receptor agonists.

ABSTRACT:

Background and purpose

Biased GPCR ligands are able to engage with their target receptor in a manner that preferentially activates distinct downstream signalling and offers potential for next generation therapeutics. However, accurate quantification of ligand bias in vitro is complex, and current best practice is not amenable for testing large numbers of compound. We have therefore sought to apply ligand bias theory to an industrial scale screening campaign for the identification of new biased μ receptor agonists.

Experimental approach

μ receptor assays with appropriate dynamic range were developed for both Gαi -dependent signalling and β-arrestin2 recruitment. Δlog(Emax /EC50 ) analysis was validated as an alternative for the operational model of agonism in calculating path

SUBMITTER: Winpenny D 

PROVIDER: S-EPMC4940816 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature