The concept of ligand-receptor binding kinetics has been broadly applied in drug development pipelines focusing on G protein-coupled receptors (GPCRs). The ligand residence time (RT) for a receptor describes how long a ligand-receptor complex exists, and is defined as the reciprocal of the dissociation rate constant (k off). RT has turned out to be a valuable parameter for GPCR researchers focusing on drug development as a good predictor of in vivo efficacy. The positive correlation between RT and in vivo efficacy has been established for several drugs targeting class A GPCRs (e.g., the neurokinin-1 receptor (NK1R), the β2 adrenergic receptor (β2AR), and the muscarinic 3 receptor (M3R)) and for drugs targeting class B1 (e.g., the glucagon-like peptide 1 receptor (GLP-1R)). Recently, the association rate constant (k on) has gained similar attention as another parameter affecting in vivo efficacy. In the current perspective, we address the importance of studying ligand-receptor binding kinetics for therapeutic targeting of GPCRs, with an emphasis on how binding kinetics can be altered by subtle molecular changes in the ligands and/or the receptors and how such changes affect treatment outcome. Moreover, we speculate on the impact of binding kinetic parameters for functional selectivity and sustained receptor signaling from endosomal compartments; phenomena that have gained increasing interest in attempts to improve therapeutic targeting of GPCRs.

中文翻译：

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观点：配体-受体结合动力学对G蛋白偶联受体的治疗靶点的影响。

配体-受体结合动力学的概念已广泛应用于专注于G蛋白偶联受体（GPCR）的药物开发流程中。受体的配体停留时间（RT）描述了配体-受体复合物存在的时间，并定义为解离速率常数的倒数（k off）。事实证明，RT是GPCR研究人员的重要参数，他们专注于将药物开发作为体内功效的良好预测指标。对于几种靶向A类GPCR的药物（例如，神经激肽1受体（NK1R），β2肾上腺素能受体（β2AR）和毒蕈碱3受体（M3R）），RT和体内功效之间存在正相关关系。靶向B1类的药物（例如胰高血糖素样肽1受体（GLP-1R））。最近，缔合速率常数（k on）作为影响体内功效的另一个参数受到了类似的关注。在当前观点下，我们致力于研究配体-受体结合动力学对于GPCR靶向治疗的重要性，重点在于如何通过配体和/或受体的细微分子变化来改变结合动力学，以及这种变化如何影响治疗结果。而且，我们推测了结合动力学参数对来自内体区室的功能选择性和持续受体信号传导的影响。人们对改善GPCR的靶向治疗的兴趣日益浓厚。重点介绍了配体和/或受体的细微分子变化如何改变结合动力学，以及这种变化如何影响治疗效果。而且，我们推测了结合动力学参数对来自内体区室的功能选择性和持续受体信号传导的影响。人们对改善GPCR的靶向治疗的兴趣日益浓厚。重点介绍了配体和/或受体的细微分子变化如何改变结合动力学，以及这种变化如何影响治疗效果。而且，我们推测了结合动力学参数对来自内体区室的功能选择性和持续受体信号传导的影响。人们对改善GPCR的靶向治疗的兴趣日益浓厚。