Davies Thomas G, Tickle Ian J
Astex Therapeutics Ltd, Cambridge, CB4 0QA, UK.
Top Curr Chem. 2012;317:33-59. doi: 10.1007/128_2011_179.
The fragment-based approach is now well established as an important component of modern drug discovery. A key part in establishing its position as a viable technique has been the development of a range of biophysical methodologies with sufficient sensitivity to detect the binding of very weakly binding molecules. X-ray crystallography was one of the first techniques demonstrated to be capable of detecting such weak binding, but historically its potential for screening was under-appreciated and impractical due to its relatively low throughput. In this chapter we discuss the various benefits associated with fragment-screening by X-ray crystallography, and describe the technical developments we have implemented to allow its routine use in drug discovery. We emphasize how this approach has allowed a much greater exploitation of crystallography than has traditionally been the case within the pharmaceutical industry, with the rapid and timely provision of structural information having maximum impact on project direction.
基于片段的方法现已成为现代药物发现的重要组成部分。确立其作为可行技术地位的一个关键因素是一系列生物物理方法的发展，这些方法具有足够的灵敏度来检测弱结合分子的结合。X射线晶体学是最早被证明能够检测这种弱结合的技术之一，但从历史上看，由于其通量相对较低，其筛选潜力未得到充分重视且不切实际。在本章中，我们讨论了通过X射线晶体学进行片段筛选的各种益处，并描述了我们为使其在药物发现中常规使用而实施的技术发展。我们强调这种方法如何使晶体学在制药行业中得到了比传统情况更大程度的利用，快速及时地提供结构信息对项目方向产生了最大影响。
