Laboratory for Biomedical Mass Spectrometry, Biosciences Institute, Newcastle University, Newcastle-upon-Tyne, NE2 4HH, UK.
Expert Rev Mol Med. 2024 Apr 12;26:e6. doi: 10.1017/erm.2024.6.
Target deconvolution can help understand how compounds exert therapeutic effects and can accelerate drug discovery by helping optimise safety and efficacy, revealing mechanisms of action, anticipate off-target effects and identifying opportunities for therapeutic expansion. Chemoproteomics, a combination of chemical biology with mass spectrometry has transformed target deconvolution. This review discusses modification-free chemoproteomic approaches that leverage the change in protein thermodynamics induced by small molecule ligand binding. Unlike modification-based methods relying on enriching specific protein targets, these approaches offer proteome-wide evaluations, driven by advancements in mass spectrometry sensitivity, increasing proteome coverage and quantitation methods. Advances in methods based on denaturation/precipitation by thermal or chemical denaturation, or by protease degradation are evaluated, emphasising the evolving landscape of chemoproteomics and its potential impact on future drug-development strategies.
靶向去卷积有助于理解化合物如何发挥治疗作用，并通过帮助优化安全性和疗效、揭示作用机制、预测脱靶效应以及识别治疗扩展机会来加速药物发现。化学蛋白质组学是化学生物学与质谱学的结合，它改变了靶向去卷积。这篇综述讨论了无修饰的化学蛋白质组学方法，这些方法利用小分子配体结合诱导的蛋白质热力学变化。与依赖于富集特定蛋白质靶标的基于修饰的方法不同，这些方法提供了基于质谱灵敏度提高的全蛋白质组评估，增加了蛋白质组覆盖范围和定量方法。评估了基于热或化学变性或蛋白酶降解的变性/沉淀的方法的进展，强调了化学蛋白质组学的不断发展及其对未来药物开发策略的潜在影响。
