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Recent advances in proteome-wide label-free target deconvolution for bioactive small molecules
Medicinal Research Reviews ( IF 10.9 ) Pub Date : 2021-02-03 , DOI: 10.1002/med.21788
Jichao Sun 1, 2 , Nayana Prabhu 3 , Jun Tang 1, 4 , Fan Yang 2, 4 , Lin Jia 5 , Jinan Guo 1 , Kefeng Xiao 1 , Wai Leong Tam 6, 7, 8, 9 , Pär Nordlund 3, 10 , Lingyun Dai 1, 2, 3
Affiliation  

Small-molecule drugs modulate biological processes and disease states through engagement of target proteins in cells. Assessing drug–target engagement on a proteome-wide scale is of utmost importance in better understanding the molecular mechanisms of action of observed beneficial and adverse effects, as well as in developing next generation tool compounds and drugs with better efficacies and specificities. However, systematic assessment of drug–target engagement has been an arduous task. With the continuous development of mass spectrometry-based proteomics instruments and techniques, various chemical proteomics approaches for drug target deconvolution (i.e., the identification of molecular target for drugs) have emerged. Among these, the label-free target deconvolution approaches that do not involve the chemical modification of compounds of interest, have gained increased attention in the community. Here we provide an overview of the basic principles and recent biological applications of the most important label-free methods including the cellular thermal shift assay, pulse proteolysis, chemical denaturant and protein precipitation, stability of proteins from rates of oxidation, drug affinity responsive target stability, limited proteolysis, and solvent-induced protein precipitation. The state-of-the-art technical implications and future outlook for the label-free approaches are also discussed.

中文翻译:

生物活性小分子全蛋白质组无标记靶标反卷积的最新进展

小分子药物通过与细胞中的靶蛋白结合来调节生物过程和疾病状态。在蛋白质组范围内评估药物-靶点参与对于更好地了解观察到的有益和不良反应的分子作用机制以及开发具有更好功效和特异性的下一代工具化合物和药物至关重要。然而,对药物靶点参与的系统评估一直是一项艰巨的任务。随着基于质谱的蛋白质组学仪器和技术的不断发展,药物靶点反卷积(即药物分子靶点的识别)的各种化学蛋白质组学方法已经出现。在这些当中,不涉及对感兴趣的化合物进行化学修饰的无标记目标反卷积方法在社区中得到了越来越多的关注。在这里,我们概述了最重要的无标记方法的基本原理和最近的生物学应用,包括细胞热位移测定、脉冲蛋白水解、化学变性剂和蛋白质沉淀、蛋白质的氧化速率稳定性、药物亲和力响应靶稳定性、有限的蛋白水解和溶剂诱导的蛋白质沉淀。还讨论了无标签方法的最新技术含义和未来前景。在这里,我们概述了最重要的无标记方法的基本原理和最近的生物学应用,包括细胞热位移测定、脉冲蛋白水解、化学变性剂和蛋白质沉淀、蛋白质的氧化速率稳定性、药物亲和力响应靶稳定性、有限的蛋白水解和溶剂诱导的蛋白质沉淀。还讨论了无标签方法的最新技术含义和未来前景。在这里,我们概述了最重要的无标记方法的基本原理和最近的生物学应用,包括细胞热位移测定、脉冲蛋白水解、化学变性剂和蛋白质沉淀、蛋白质的氧化速率稳定性、药物亲和力响应靶稳定性、有限的蛋白水解和溶剂诱导的蛋白质沉淀。还讨论了无标签方法的最新技术含义和未来前景。
更新日期:2021-02-03
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