Proteins are the main targets of most drugs; however, system-wide methods to monitor protein activity and function are still underused in drug discovery. Novel biochemical approaches, in combination with recent developments in mass spectrometry-based proteomics instrumentation and data analysis pipelines, have now enabled the dissection of disease phenotypes and their modulation by bioactive molecules at unprecedented resolution and dimensionality. In this Review, we describe proteomics and chemoproteomics approaches for target identification and validation, as well as for identification of safety hazards. We discuss innovative strategies in early-stage drug discovery in which proteomics approaches generate unique insights, such as targeted protein degradation and the use of reactive fragments, and provide guidance for experimental strategies crucial for success.

蛋白质是大多数药物的主要靶点；然而，监测蛋白质活性和功能的全系统方法在药物发现中仍未得到充分利用。新的生化方法，结合基于质谱的蛋白质组学仪器和数据分析管道的最新发展，现在能够以前所未有的分辨率和维度对疾病表型及其通过生物活性分子进行的调节进行剖析。在这篇综述中，我们描述了用于目标识别和验证以及安全隐患识别的蛋白质组学和化学蛋白质组学方法。我们讨论了早期药物发现中的创新策略，其中蛋白质组学方法产生了独特的见解，例如靶向蛋白质降解和反应性片段的使用，