Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Magyar tudósok krt. 2, H-1117 Budapest, Hungary.
Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Magyar tudósok krt. 2, H-1117 Budapest, Hungary.
Drug Discov Today. 2020 Jun;25(6):983-996. doi: 10.1016/j.drudis.2020.03.016. Epub 2020 Apr 13.
Targeted covalent inhibitors and chemical probes have become integral parts of drug discovery approaches. Given the advantages of fragment-based drug discovery, screening electrophilic fragments emerged as a promising alternative to discover and validate novel targets and to generate viable chemical starting points even for targets that are barely tractable. In this review, we present recent principles and considerations in the design of electrophilic fragment libraries from the selection of the appropriate covalent warhead through the design of the covalent fragment to the compilation of the library. We then summarize recent screening methodologies of covalent fragments against surrogate models, proteins, and the whole proteome, or living cells. Finally, we highlight recent drug discovery applications of covalent fragment libraries.
靶向共价抑制剂和化学探针已成为药物发现方法的重要组成部分。鉴于基于片段的药物发现的优势，筛选亲电片段成为发现和验证新靶标并生成可行化学起点的有前途的替代方法，即使对于几乎难以处理的靶标也是如此。在这篇综述中，我们介绍了从选择合适的共价弹头，通过设计共价片段到库的编译，设计亲电片段库的最新原则和注意事项。然后，我们总结了针对替代模型、蛋白质和整个蛋白质组或活细胞的共价片段的最新筛选方法。最后，我们强调了共价片段文库在药物发现中的最新应用。
