Orita Masaya, Ohno Kazuki, Warizaya Masaichi, Amano Yasushi, Niimi Tatsuya
Chemistry for Leads, Chemistry Research Labs, Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki, Japan.
Methods Enzymol. 2011;493:383-419. doi: 10.1016/B978-0-12-381274-2.00015-7.
In fragment-based drug discovery (FBDD), not only identifying the starting fragment hit to be developed but also generating a drug lead from that starting fragment hit is important. Converting fragment hits to leads is generally similar to a high-throughput screening (HTS) hits-to-leads approach in that properties associated with activity for a target protein, such as selectivity against other targets and absorption, distribution, metabolism, excretion, and toxicity (ADME/Tox), and physicochemical properties should be taken into account. However, enhancing the potency of the fragment hit is a key requirement in FBDD, unlike HTS, because initial fragment hits are generally weak. This enhancement is presently achieved by adding additional chemical groups which bind to additional parts of the target protein or by joining or combining two or more hit fragments; however, strategies for effecting greater improvements in effective activity are needed. X-ray analysis is a key technology attractive for converting fragments to drug leads. This method makes it clear whether a fragment hit can act as an anchor and provides insight regarding introduction of functional groups to improve fragment activity. Data on follow-up chemical synthesis of fragment hits has allowed for the differentiation of four different strategies: fragment optimization, fragment linking, fragment self-assembly, and fragment evolution. Here, we discuss our opinion regarding how to follow up on fragment hits, with a focus on the importance of fragment hits as an anchor moiety to so-called hot spots in the target protein using crystallographic data.
在基于片段的药物发现（FBDD）中，不仅识别待开发的起始片段命中物很重要，而且从该起始片段命中物生成药物先导物也很重要。将片段命中物转化为先导物通常类似于高通量筛选（HTS）的命中物到先导物方法，即应考虑与靶蛋白活性相关的特性，如对其他靶标的选择性以及吸收、分布、代谢、排泄和毒性（ADME/Tox），还有物理化学性质。然而，与HTS不同，提高片段命中物的效力是FBDD中的关键要求，因为初始片段命中物通常活性较弱。目前，这种增强是通过添加与靶蛋白其他部分结合的额外化学基团，或通过连接或组合两个或更多命中片段来实现的；然而，需要能够在有效活性方面实现更大改进的策略。X射线分析是一种将片段转化为药物先导物的极具吸引力的关键技术。该方法能明确一个片段命中物是否可作为锚定物，并为引入官能团以改善片段活性提供见解。关于片段命中物后续化学合成的数据使得区分四种不同策略成为可能：片段优化、片段连接、片段自组装和片段进化。在此，我们讨论关于如何跟进片段命中物的观点，重点是利用晶体学数据，将片段命中物作为靶蛋白中所谓热点的锚定部分的重要性。
