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

机译：基于胶体聚集体检测和自然产物滥用表征的谐振波导光栅

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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：将含水缓冲液中的小分子，包括自然化合物，即自我递入胶体聚集体是药物发现早期阶段的错误结果的主要原因。这里我们报道了基于谐振波导光栅（RWG）的测定以鉴定天然化合物聚集并表征其对活细胞中膜受体的影响。我们首先施加无细胞聚集测定以确定复合临界聚集浓度（CAC）值。然后，我们用三种类型的动态分配（DMR）测定表征聚集器对膜受体的影响。结果表明，胶体聚集体可引起DMR脱敏测定中的假活性;可以通过DMR激动症测定中的大响应来暗示一些假活性，并且可以通过DMR拮抗作用方法鉴定。此外，通过加入0.025％的Tween-80确认聚集机制，细胞信号衰减和效力降低。最后，这些观察结果用于传统草药的骨料检查和滥交调查Rhodiola Rosea，最终导致了真正的目标并降低了第一阶段的生物活性跟踪过程的风险。本研究强调了基于RWG的测定可以用作实用工具，以区分真实和虚假的命中，以提供药物发现的早期阶段的可靠结果。

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    《RSC Advances》 |2019年第65期|共10页
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  • 正文语种 eng
  • 中图分类 化学;
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