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Drug Discov Today. 2016 Jan;21(1):90-96. doi: 10.1016/j.drudis.2015.07.015. Epub 2015 Jul 28.

Can residence time offer a useful strategy to target agonist drugs for sustained GPCR responses?

Author information

1
AstraZeneca, Discovery Sciences, Alderley Park, Macclesfield SK10 4TG, UK.
2
Heptares Therapeutics, Welwyn Garden City AL7 3AX, UK.
3
AstraZeneca, Discovery Sciences, Cambridge Science Park, Cambridge CB4 0WG, UK.
4
AstraZeneca, Discovery Sciences, Cambridge Science Park, Cambridge CB4 0WG, UK. Electronic address: philip.rawlins@astrazeneca.com.

Abstract

Residence time describes the how long a ligand is bound to its target, and is attracting interest in drug discovery as a potential means of improving clinical efficacy by increasing target coverage. This concept, as originally applied to antagonists, is more complicated for G-protein-coupled receptor (GPCR) agonists because of the transiency of receptor responses (via desensitization and internalization). However, in some cases sustained GPCR agonist responses have been observed, with evidence consistent with a role for slow binding kinetics. We propose a model to explain our understanding of how residence time and rebinding might influence sustained signaling by internalized receptors. We also highlight the anticipated benefit for drug discovery of fully understanding and exploiting these phenomena to target desirable receptor response profiles selectively.

PMID:
26226643
DOI:
10.1016/j.drudis.2015.07.015
[Indexed for MEDLINE]
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