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Target immobilization and NMR screening of fragments in early drug discovery

机译：早期药物发现中的目标固定和片段的NMR筛选

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Using localized NMR spectroscopy on immobilized targets provides us with a method to simultaneously assess binding of small molecules to two different samples. This Target Immobilized NMR Screening (TINS) has a number of advantages, not least is the requirement for minimal quantities of non-isotopically labeled protein and the applicability to insoluble or unstable targets. The technique is sensitive to binding with KD values in the range of 100 nM to 20 mM, while careful selection of the reference protein reduces the number of false positive hits. This combination ensures a maximal number of valid hits from which to select starting points for hit elaboration projects. Hits can be prioritized using biological assays when appropriate, as well as an array of biophysical techniques. So far a variety of soluble proteins, including kinases, GTPases, viral targets and proteases, as well as a membrane protein, have been successfully screened against our fragment library. Here we illustrate our experiences with a number of examples which emphasize the usefulness of the method in selecting and prioritizing fragment hits for elaboration towards leads.
机译：在固定的目标上使用局部NMR光谱学为我们提供了一种同时评估小分子与两个不同样品结合的方法。这种固定靶标的NMR筛查（TINS）具有许多优点，尤其是对最少量的非同位素标记蛋白的要求以及对不溶或不稳定靶标的适用性。该技术对与100 nM至20 mM范围内的KD值结合敏感，而仔细选择参考蛋白可减少假阳性结果的数量。这种组合可确保最大数量的有效命中，从中可以为命中制作项目选择起点。可以在适当的时候使用生物测定法以及一系列生物物理技术对命中进行优先排序。到目前为止，已经针对我们的片段文库成功筛选了各种可溶性蛋白，包括激酶，GTP酶，病毒靶标和蛋白酶以及膜蛋白。在这里，我们通过许多示例来说明我们的经验，这些示例强调了该方法在选择片段命中和确定片段优先顺序以进行潜在客户化方面的作用。

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