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Resonant waveguide grating based assays for colloidal aggregate detection and promiscuity characterization in natural products

机译：基于共振波导光栅的天然产物胶体聚集体检测和混杂特征分析

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Small molecules, including natural compounds, in aqueous buffer that self-associate into colloidal aggregates is the main cause of false results in the early stage of drug discovery. Here we reported resonant waveguide grating (RWG) based assays to identify natural compound aggregation and characterize its influence on membrane receptors in living cells. We first applied a cell-free aggregation assay to determine compound critical aggregation concentration (CAC) values. Then we characterized the aggregators' influence on membrane receptors using three types of dynamic mass redistribution (DMR) assays. Results showed that colloidal aggregates may cause false activity in DMR desensitization assays; some of the false activities can be implied by the large response in DMR agonism assays and can further be identified by DMR antagonism assays. Furthermore, the aggregation mechanism was confirmed by addition of 0.025% tween-80, with cell signals attenuated and potency decreased. Finally, these observations were used for aggregate examination and promiscuity investigation of a traditional herbal medicine, Rhodiola rosea , which ultimately led to the revealing of the true target and reduced the risk of a bioactivity tracking process at the very first stage. This study highlights that the RWG based assays can be used as practical tools to distinguish between real and false hits to provide reliable results in the early stage of drug discovery.
机译：自缔合成胶体聚集体的水性缓冲液中的小分子，包括天然化合物，是药物发现早期错误结果的主要原因。在这里，我们报道了基于共振波导光栅（RWG）的检测方法，以鉴定天然化合物的聚集并表征其对活细胞中膜受体的影响。我们首先应用无细胞聚集测定法来确定化合物临界聚集浓度（CAC）值。然后，我们使用三种类型的动态质量重新分布（DMR）分析来表征聚集器对膜受体的影响。结果表明，胶体聚集体可能在DMR脱敏试验中引起假活性。 DMR激动试验中的大量反应可能暗示了某些错误的活动，而DMR拮抗试验则可以进一步鉴定。此外，通过添加0.025％tween-80证实了聚集机制，其中细胞信号减弱并且效力降低。最后，这些观察结果用于对传统草药玫瑰红景天的综合检查和滥交调查，最终导致揭示了真正的目标，并在最初阶段降低了生物活性追踪过程的风险。这项研究强调，基于RWG的测定可用作实用工具，以区分真假和假假，以在药物发现的早期阶段提供可靠的结果。

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