Exposing Small-Molecule Nanoentities by a Nuclear Magnetic Resonance Relaxation Assay
Exposing Small-Molecule Nanoentities by a Nuclear Magnetic Resonance Relaxation Assay
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DOI：
10.1021/acs.jmedchem.9b00653
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发表时间：
2019-09-12
影响因子：
7.3
通讯作者：
LaPlante, Steven R.
中科院分区：
文献类型：
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作者：
Ayotte, Yann;Marando, Victoria M.;LaPlante, Steven R.
小分子可以在水溶液中自组装成各种各样的纳米实体类型和尺寸（二聚体、n聚体、胶束、胶体等），每一种都有其独特的性质。这在药物发现的背景下具有重要的后果，包括与非特异性结合、脱靶效应以及假阳性和假阴性相关的问题。在这里，我们证明了自旋自旋弛豫Carr-Purcell-Meiboom-Gill NMR实验的使用，该实验对分子翻滚速率敏感，并且可以暴露具有较慢旋转相关性的较大聚集体物种。该策略很容易区分孤独翻滚分子与各种大小的纳米实体。该技术对单分子和聚集体状态之间的化学交换高度敏感，因此可以用作报告者，当通过NMR无法直接测量聚集体时。有趣的是，我们发现结构相关系列内化合物的溶液行为存在差异，表明了结构-纳米实体关系。这个实际的实验是一个有价值的工具，以支持药物发现的努力。
Small molecules can self-assemble in aqueous solution into a wide range of nanoentity types and sizes (dimers, n-mers, micelles, colloids, etc.), each having their own unique properties. This has important consequences in the context of drug discovery including issues related to nonspecific binding, off target effects, and false positives and negatives. Here, we demonstrate the use of the spin spin relaxation Carr-Purcell-Meiboom-Gill NMR experiment, which is sensitive to molecular tumbling rates and can expose larger aggregate species that have slower rotational correlations. The strategy easily distinguishes lone-tumbling molecules versus nanoentities of various sizes. The technique is highly sensitive to chemical exchange between single molecule and aggregate states and can therefore be used as a reporter when direct measurement of aggregates is not possible by NMR Interestingly, we found differences in solution behavior for compounds within structurally related series, demonstrating structure-nanoentity relationships. This practical experiment is a valuable tool to support drug discovery efforts.