Exiting the tunnel of uncertainty: crystal soak to validated hit.
Exiting the tunnel of uncertainty: crystal soak to validated hit.
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DOI：
10.1107/s2059798322009986
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发表时间：
2022-11-01
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简要概述了在命中识别/验证阶段的药物发现中使用的技术，突出了正交测量和三角测量在早期阶段的晶体命中验证的重要性。晶体学片段筛选提供了一种高效和有效的方法来鉴定结晶蛋白质的小分子配体。由于它们的低分子量，这样的命中倾向于对其靶具有低的、通常不可量化的亲和力，使得验证命中作为靶的真实溶液相配体和鉴定“最佳”命中以用于进一步加工的双重挑战复杂化。在这篇文章中，解决这些挑战的方法进行评估。使用回顾性分析最近的ATAD 2命中识别活动，以及其他成功的片段筛选活动的例子，它建议，命中验证和优先级最好实现的“三角”的方法，其中多个可用的生化和生物物理技术的结果相关联，以开发定性的结构-活性关系（SAR）。这种定性的SAR可能确实是唯一的手段，通过隧道的不确定性，普遍存在的规模生物物理，生物化学和/或生物测量成为可能之前，导航一个项目。
A brief overview of techniques used in the hit-identification/validation stage of drug discovery is given, highlighting the importance of orthogonal measurements and triangulation in early-stage crystallographic hit validation. Crystallographic fragment screens provide an efficient and effective way to identify small-molecule ligands of a crystallized protein. Due to their low molecular weight, such hits tend to have low, often unquantifiable, affinity for their target, complicating the twin challenges of validating the hits as authentic solution-phase ligands of the target and identifying the ‘best’ hit(s) for further elaboration. In this article, approaches that address these challenges are assessed. Using retrospective analysis of a recent ATAD2 hit-identification campaign, alongside other examples of successful fragment-screening campaigns, it is suggested that hit validation and prioritization are best achieved by a ‘triangulation’ approach in which the results of multiple available biochemical and biophysical techniques are correlated to develop qualitative structure–activity relationships (SARs). Such qualitative SARs may indeed be the only means by which to navigate a project through the tunnel of uncertainty that prevails before on-scale biophysical, biochemical and/or biological measurements become possible.
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作者：
Roy A
通讯作者：
Roy A