University of Cambridge Department of Chemistry, Cambridge, UK.
The Francis Crick Institute, London, UK.
Chem Biol Drug Des. 2022 Oct;100(4):469-486. doi: 10.1111/cbdd.14120. Epub 2022 Aug 16.
Fragment-based drug discovery (FBDD) is a method of identifying small molecule hits that can be elaborated rationally through fragment growing, merging and linking, to afford high-affinity ligands for biological targets. Despite the promised theoretical potential of fragment linking, examples are still surprisingly sparse and remain overshadowed by the successes of fragment growing. The aim of this review was to outline a number of key examples of fragment-linking strategies and discuss their strengths and limitations. Structure-based approaches including X-ray crystallography and in silico methods of fragment optimization are discussed, as well as fragment linking guided by NMR experiments. Target-guided approaches, exploiting the biological target to assemble its own inhibitors through dynamic combinatorial chemistry (DCC) and kinetic target-guided synthesis (KTGS), are identified as alternative efficient methods for fragment linking.
基于片段的药物发现（FBDD）是一种识别小分子命中的方法，可以通过片段生长、融合和连接进行合理的阐述，从而为生物靶标提供高亲和力的配体。尽管片段连接具有理论上的潜力，但实例仍然非常稀少，并且仍然被片段生长的成功所掩盖。本文的目的是概述一些关键的片段连接策略的例子，并讨论它们的优缺点。讨论了基于结构的方法，包括 X 射线晶体学和基于计算机的片段优化方法，以及通过 NMR 实验指导的片段连接。靶向导向的方法，利用生物靶标通过动态组合化学（DCC）和动力学靶标导向合成（KTGS）组装其自身的抑制剂，被确定为片段连接的替代有效方法。
