There are clearly many different philosophies associated with adapting fragment screening into mainstream Drug Discovery Lead Generation strategies. Scientists at Astex, for instance, focus entirely on strategies involving use of X-ray crystallography and NMR. However, AstraZeneca uses a number of different fragment screening strategies. One approach is to screen a 2000 compound fragment set (with close to "lead-like" complexity) at 100 microM in parallel with every HTS such that the data are obtained on the entire screening collection at 10 microM plus the extra samples at 100 microM; this provides valuable compound potency data in a concentration range that is usually unexplored. The fragments are then screen-specific "privileged structures" that can be searched for in the rest of the HTS output and other databases as well as having synthesis follow-up. A typical workflow for a fragment screen within AstraZeneca is shown below (Figure 24) and highlights the desirability (particularly when screening >100 microM) for NMR and X-ray information to validate weak hits and give information on how to optimise them. In this chapter, we have provided an introduction to the theoretical and practical issues associated with the use of fragment methods and lead-likeness. Fragment-based approaches are still in an early stage of development and are just one of many interrelated techniques that are now used to identify novel lead compounds for drug development. Fragment based screening has some advantages, but like every other drug hunting strategy will not be universally applicable. There are in particular some practical challenges associated with fragment screening that relate to the generally lower level of potency that such compounds initially possess. Considerable synthetic effort has to be applied for post-fragment screening to build the sort of potency that would be expected to be found from a traditional HTS. However, if there are no low-hanging fruit in a screening collection to be found by HTS then the use of fragment screening can help find novelty that may lead to a target not being discarded as intractable. As such, the approach offers some significant advantages by providing less complex molecules, which may have better potential for novel drug optimisation and by enabling new chemical space to be more effectively explored. Many literature examples that cover examples of fragment screening approaches are still at the "proof of concept" stage and although delivering inhibitors or ligands, may still prove to be unsuitable when further ADMET and toxicity profiling is done. The next few years should see a maturing of the area, and as our understanding of how the concepts can be best applied, there are likely to be many more examples of attractive, small molecule hits, leads and candidate drugs derived from the approaches described.

中文翻译：

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片段筛选：简介。

显然，有许多与将片段筛选应用于主流药物发现潜在顾客生成策略相关的哲学。例如，Astex的科学家完全专注于涉及使用X射线晶体学和NMR的策略。但是，阿斯利康使用多种不同的片段筛选策略。一种方法是与每个HTS并行地筛选100 microM的2000个化合物片段集（具有接近“铅样”的复杂度），从而在整个筛选集合中获得10 microM的数据以及额外的100 microM样品; 这提供了通常无法探索的浓度范围内有价值的化合物效价数据。然后，这些片段是特定于屏幕的“特权结构” 可以在HTS输出的其余部分和其他数据库中进行搜索，并且可以进行综合跟踪。下图（图24）显示了阿斯利康内碎片筛查的典型工作流程，并着重指出了对NMR和X射线信息进行验证（尤其是筛选> 100 microM时）的可取性，以验证弱点击并提供有关如何优化它们的信息。在本章中，我们对与片段方法的使用和潜在客户相似性相关的理论和实践问题进行了介绍。基于片段的方法仍处于开发的早期阶段，只是许多相互关联的技术中的一种，目前已用于鉴定用于药物开发的新型先导化合物。基于片段的筛查具有一些优势，但与其他所有的药物狩猎策略一样，它不会普遍适用。特别地，与片段筛选有关的一些实际挑战涉及这类化合物最初具有的通常较低的效力水平。对于碎片后筛选，必须进行大量的合成工作，以建立可以从传统HTS中发现的效能。但是，如果在HTS的筛查中没有发现低落的果实，那么使用片段筛查可以帮助发现新颖性，从而可能导致目标无法被视为难以处理而被丢弃。这样，该方法通过提供较少复杂的分子而提供了一些显着的优势，这些分子对于新药的优化可能具有更好的潜力，并且通过使新的化学空间得以更有效地探索。许多涵盖片段筛选方法实例的文献实例仍处于“概念验证”阶段，尽管提供抑制剂或配体，但在进行进一步的ADMET和毒性分析后可能仍不适合。未来几年，该领域将逐渐成熟，随着我们对如何最好地应用这些概念的理解，可能还会有更多来自所述方法的有吸引力的小分子药物，潜在客户和候选药物的例子。