目的:受体作用的经典理论已被用作评估配体诱导的受体激活的分子决定子的有力工具(即,亲和力和功效)来自实验可观察到的生物反应。然而,受体结合和激活机制,及其参数,经典理论中描述的与基于变构原理的受体激活的现代观点相矛盾。
方法:我们使用数学分析,以及一些数值模拟,回答关键问题,即经典理论在多大程度上与现代对受体激活的理解相容。
结果:这里,我们最终证明(1)基于变构原理的受体激活方程包含了经典理论的逻辑,因此,(2)通过经典技术获得的“内在功效”(ε)的估计(即,零方法或将操作模型拟合到浓度-响应数据)等效于代表配体分子功效的变构耦合因子。
结论:因此,我们得出的结论是,尽管迄今为止它受到了合理的批评,经典理论可能继续有助于从实验数据中估计配体功效,如果使用得当。这里,我们还为正确使用该理论提供了严格的标准。这些发现不仅对配体分类有意义,而且还解决了GPCR中偏倚激动领域的一些长期讨论,这需要合理估计不同信号通路的相对配体效力。
OBJECTIVE: The classical theory of receptor action has been used for decades as a powerful tool to estimate molecular determinants of ligand-induced receptor activation (i.e., affinity and efficacy) from experimentally observable biological responses. However, it is also a well-recognized fact that the receptor-binding and activation mechanisms, and the parameters thereof, described in the classical theory contradict with the modern view of receptor activation based on allosteric principles.
METHODS: We used mathematical analysis, along with some numerical simulations, to answer the key question as to what extent the classical theory is compatible-if at all-with the modern understanding of receptor activation.
RESULTS: Here, we showed conclusively that (1) receptor activation equations based on allosteric principles contain the logic of the classical theory in disguise, and therefore, (2) estimates of \"intrinsic efficacy\" (ε) obtained by means of classical techniques (i.e., null methods or fitting the operational model to concentration-response data) are equivalent to the allosteric coupling factors that represent the molecular efficacy of ligands.
CONCLUSIONS: Thus, we conclude that despite the justified criticisms it has received so far, the classical theory may continue to be useful in estimating ligand efficacy from experimental data, if used properly. Here, we also provide rigorous criteria for the proper use of the theory. These findings not only have implications for ligand classification but also resolve some long lasting discussions in the field of bias
agonism in GPCR, which requires reasonable estimates of relative ligand efficacies at different signalling pathways.