共价药物已被用于治疗疾病超过一个世纪，但是促进合理设计共价药物的工具是最近才出现的。通过有意向现有配体中添加反应性的功能基团，可以实现对靶蛋白的强效选择性抑制，这已经通过共价表皮生长因子受体（EGFR）和布氏酪氨酸激酶（BTK）抑制剂治疗不同类型的癌症得到证明。此外，“亲电子优先”方法鉴定共价配体，也导致了共价药物的发现，例如针对KRAS（G12C）和SARS-CoV-2主蛋白酶的共价抑制剂。特别是，KRAS（G12C）抑制剂的发现验证了共价筛选技术的使用，这些技术在过去十年中变得更加强大和广泛。化学蛋白质组学平台出现了，以补充共价配体筛选，并协助配体发现、选择性分析和靶标鉴定。本文回顾了共价药物发现的里程碑，强调了这些计划所学到的经验以及共价药物发现技术不断发展的工具箱如何促进了该领域的成功。©2022. Springer Nature Limited.

Covalent drugs have been used to treat diseases for more than a century, but tools that facilitate the rational design of covalent drugs have emerged more recently. The purposeful addition of reactive functional groups to existing ligands can enable potent and selective inhibition of target proteins, as demonstrated by the covalent epidermal growth factor receptor (EGFR) and Bruton's tyrosine kinase (BTK) inhibitors used to treat various cancers. Moreover, the identification of covalent ligands through 'electrophile-first' approaches has also led to the discovery of covalent drugs, such as covalent inhibitors for KRAS(G12C) and SARS-CoV-2 main protease. In particular, the discovery of KRAS(G12C) inhibitors validates the use of covalent screening technologies, which have become more powerful and widespread over the past decade. Chemoproteomics platforms have emerged to complement covalent ligand screening and assist in ligand discovery, selectivity profiling and target identification. This Review showcases covalent drug discovery milestones with emphasis on the lessons learned from these programmes and how an evolving toolbox of covalent drug discovery techniques facilitates success in this field.© 2022. Springer Nature Limited.