A ligand that acts on a target receptor to activate particular multiple signalling pathways with activity that is distinct from other ligands is termed ligand bias. Quantification of ligand bias is based on applying the operational model to each pathway separately and subsequent calculation of the ligand bias metric (ΔΔlogR). This approach implies independence among different pathways and causes propagation of error in the calculation. Here, we propose a semi-mechanism-based model which allows for receptor selectivity across all the pathways simultaneously (termed the ‘intact operational model’). The power of the intact model for detecting ligand bias was evaluated via stochastic simulation estimation studies. It was also applied to two examples: (1) opposing effects of Gi/Gs signalling of α2-adrenergic receptors and (2) simultaneous measurement of arachidonic acid release and inositol phosphate accumulation following 5-HT_2C receptor activation. The intact operational model demonstrated greater power to detect ligand bias in the simulation. In the applications, it provided better precision of estimation and identified biased ligands that were missed by analysis of traditional methods. Issues identified in both examples might lead to different interpretations of the data. The intact operational model may elucidate greater understanding of the underlying mechanisms of functional selectivity.

作用于靶受体以激活具有不同于其他配体活性的特定多个信号传导途径的配体称为配体偏倚。配体偏倚的定量基于将操作模型分别应用于每个途径并随后计算配体偏倚度量（ΔΔlogR）。这种方法意味着不同途径之间的独立性，并导致计算误差的传播。在这里，我们提出了一种基于半机制的模型，该模型允许同时跨所有途径进行受体选择性（称为“完整操作模型”）。通过随机模拟估计研究评估了完整模型检测配体偏倚的能力。它也适用于两个示例：（1）α2-肾上腺素能受体的Gi / Gs信号传导的相反作用；（2）5-HT _2C后同时测量花生四烯酸的释放和肌醇磷酸盐的积累受体激活。完整的操作模型证明了在仿真中具有更大的检测配体偏倚的能力。在应用中，它提供了更好的估计精度，并鉴定了传统方法分析所遗漏的有偏配体。两个示例中确定的问题可能导致对数据的不同解释。完整的操作模型可以阐明对功能选择性潜在机制的更多理解。