Hot-Spotting with Thermal Scanning: A Ligand- and Structure-Independent Assessment of Target Ligandability
Hot-Spotting with Thermal Scanning: A Ligand- and Structure-Independent Assessment of Target Ligandability
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DOI：
10.1021/acs.jmedchem.7b00208
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发表时间：
2017-06-22
影响因子：
7.3
通讯作者：
Geschwindner, Stefan
中科院分区：
文献类型：
--
作者：
Chilton, Molly;Clennell, Ben;Geschwindner, Stefan
评估蛋白质靶标的配基能力是确定命中寻找策略或在药物靶标中确定优先顺序时的关键组成部分。基于核磁共振(核磁共振)片段筛选的计算和生物物理方法是有效的方法，但受到限制其使用的特定限制。在这里，我们展示了高通量热扫描(HTTS)作为一种简单和通用的生物物理片段筛选方法的适用性，以复制基于核磁共振筛选的评估。通过将这种方法应用于一大组蛋白质，我们可以进一步表明，该评估是高通量筛选(HTS)成功的预测。对于低配位性靶标的少数分歧源于正交化生物物理方法的敏感性差异。因此，我们应用了一种新的策略，利用溶剂结构中的调制来提高检测的灵敏度。这一新方法能够改进配基能力评估：与基于核磁共振的评估一致，更重要的是，将该方法定位为生物物理片段筛选的有价值的选择。
Evaluating the ligandability of a protein target is a key component when defining hit-finding strategies or when prioritize among drug targets. Computational as well as biophysical approaches based on nuclear magnetic resonance (NMR) fragment screening are powerful approaches but suffer from specific constraints that limit their usage. Here, we demonstrate the applicability of high-throughput thermal scanning (HTTS) as a simple and generic biophysical fragment screening method to reproduce assessments from NMR-based screening. By applying this method to a large set of proteins we can furthermore show that the assessment is predictive of the success of high-throughput screening (HTS). The few divergences for targets of low ligandability originate from the sensitivity differences of the orthogonal biophysical methods. We thus applied a new strategy making use of modulations in the solvent structure to improve assay sensitivity. This novel approach enables improved ligandability assessments :in accordance with NMR-based assessments and more importantly-positions the methodology as a valuable option for biophysical fragment screening.