title: Can residence time offer a useful strategy to target agonist drugs for sustained GPCR responses?
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.
authors.affiliation: AstraZeneca, Discovery Sciences, Alderley Park, Macclesfield SK10 4TG, UK.
authors.forename: J Daniel
authors.initials: JD
authors.lastname: Hothersall
authors.affiliation: Heptares Therapeutics, Welwyn Garden City AL7 3AX, UK.
authors.forename: Alastair J
authors.initials: AJ
authors.lastname: Brown
authors.affiliation: AstraZeneca, Discovery Sciences, Cambridge Science Park, Cambridge CB4 0WG, UK.
authors.forename: Ian
authors.initials: I
authors.lastname: Dale
authors.affiliation: AstraZeneca, Discovery Sciences, Cambridge Science Park, Cambridge CB4 0WG, UK. Electronic address: philip.rawlins@astrazeneca.com.
authors.forename: Philip
authors.initials: P
authors.lastname: Rawlins
mesh_terms: D055808:Drug Discovery / Q000379:methods*; D007700:Kinetics; D008024:Ligands; D011485:Protein Binding / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D008024:Ligands; D043562:Receptors, G-Protein-Coupled