G蛋白偶联受体
兴奋剂
内化
药物发现
受体
脱敏(药物)
药理学
药品
停留时间(流体动力学)
计算生物学
化学
医学
生物
生物信息学
生物化学
工程类
岩土工程
作者
Joanne Hothersall,Alastair Brown,Ian L. Dale,Philip Rawlins
标识
DOI:10.1016/j.drudis.2015.07.015
摘要
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.
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