The rise of fragment-based drug discovery
The rise of fragment-based drug discovery
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DOI：
10.1038/nchem.217
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发表时间：
2009-06-01
期刊：
影响因子：
21.8
通讯作者：
Rees, David C.
中科院分区：
文献类型：
--
作者：
Murray, Christopher W.;Rees, David C.
新药的研究在研发的各个阶段都受到高损耗率的困扰。化学家有机会解决这个问题，因为磨损可以部分追溯到化学品的质量。基于片段的药物发现（FBDD）是一种新的方法，越来越多地用于制药行业，用于减少损耗并为以前难以解决的生物靶点提供线索。FBDD识别与生物学上重要的大分子结合的低分子量配体（类似于150 Da）。使用X射线晶体学或NMR光谱法确定这些片段的三维实验结合模式，并用于促进其优化为具有药物样性质的有效分子。与高通量筛选相比，片段方法需要筛选更少的化合物，并且尽管筛选命中的初始效力较低，但提供了更有效且富有成效的优化活动。在这里，我们回顾了FBDD的兴起，包括它在发现其他化学方法一直在努力的临床候选目标方面的应用。
The search for new drugs is plagued by high attrition rates at all stages in research and development. Chemists have an opportunity to tackle this problem because attrition can be traced back, in part, to the quality of the chemical leads. Fragment-based drug discovery (FBDD) is a new approach, increasingly used in the pharmaceutical industry, for reducing attrition and providing leads for previously intractable biological targets. FBDD identifies low-molecular-weight ligands (similar to 150 Da) that bind to biologically important macromolecules. The three-dimensional experimental binding mode of these fragments is determined using X-ray crystallography or NMR spectroscopy, and is used to facilitate their optimization into potent molecules with drug-like properties. Compared with high-throughput-screening, the fragment approach requires fewer compounds to be screened, and, despite the lower initial potency of the screening hits, offers more efficient and fruitful optimization campaigns. Here, we review the rise of FBDD, including its application to discovering clinical candidates against targets for which other chemistry approaches have struggled.