Finding the Perfect Fit: Conformational Biosensors to Determine the Efficacy of GPCR Ligands.
Finding the Perfect Fit: Conformational Biosensors to Determine the Efficacy of GPCR Ligands.
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DOI：
10.1021/acsptsci.1c00256
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发表时间：
2022-08
影响因子：
6
通讯作者：
Keith M Olson;Andra Campbell;A. Alt;J. Traynor
中科院分区：
文献类型：
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作者：
Keith M Olson;Andra Campbell;A. Alt;J. Traynor
G蛋白偶联受体（gpcr）是具有多种构象的高度可药物靶点。配体稳定其同源受体特定构象的能力决定了其产生生物反应的功效或能力。识别产生不同受体构象和潜在离散药理作用的配体（例如，偏倚激动剂、部分激动剂、拮抗剂、变构调节剂）是药物发现的主要目标，也是开发疗效更好、副作用更少的药物的必要条件。幸运的是，随着构象生物传感器的最新发展，通过受体构象变化直接测量配体功效成为可能。本文综述了两态模型、三元复合模型和多态模型等经典的疗效模型。我们描述了基于纳米体、传感器和受体的构象生物传感器如何检测和/或稳定特定的GPCR构象，以识别具有不同功效水平的配体。特别是，构象生物传感器提供了识别和/或表征治疗所需的潜力，但通常难以比目前的方法更快更好地测量受体的构象。对于药物发现/开发，最近的几项原理验证研究优化了用于高通量筛选（HTS）平台的构象生物传感器。然而，它们的广泛使用受到以下事实的限制：很少有传感器能够可靠地检测低频构象和技术要求苛刻的分析条件。尽管如此，构象生物传感器确实有助于在单次分析中识别理想的配体，如变构调节剂、偏配体或部分激动剂，这比传统方法具有明显的优势。
G protein-coupled receptors (GPCRs) are highly druggable targets that adopt numerous conformations. A ligand's ability to stabilize specific conformation(s) of its cognate receptor determines its efficacy or ability to produce a biological response. Identifying ligands that produce different receptor conformations and potentially discrete pharmacological effects (e.g., biased agonists, partial agonists, antagonists, allosteric modulators) is a major goal in drug discovery and necessary to develop drugs with better effectiveness and fewer side effects. Fortunately, direct measurements of ligand efficacy, via receptor conformational changes are possible with the recent development of conformational biosensors. In this review, we discuss classical efficacy models, including the two-state model, the ternary-complex model, and multistate models. We describe how nanobody-, transducer-, and receptor-based conformational biosensors detect and/or stabilize specific GPCR conformations to identify ligands with different levels of efficacy. In particular, conformational biosensors provide the potential to identify and/or characterize therapeutically desirable but often difficult to measure conformations of receptors faster and better than current methods. For drug discovery/development, several recent proof-of-principle studies have optimized conformational biosensors for high-throughput screening (HTS) platforms. However, their widespread use is limited by the fact that few sensors are reliably capable of detecting low-frequency conformations and technically demanding assay conditions. Nonetheless, conformational biosensors do help identify desirable ligands such as allosteric modulators, biased ligands, or partial agonists in a single assay, representing a distinct advantage over classical methods.