Advanced bioanalytical mass spectrometry methods for investigating protein covalent binding by reactive metabolites

药物代谢的主要作用是使身体从外源性物质中解毒，使它们更具极性，从而更容易清除。然而，一些药物被生物活化成具有与蛋白质共价结合的潜力的活性代谢物。这种结合被认为是特异质药物反应（IDR）的重要原因。因此，反应性代谢物的形成代表了药物化合物的重大责任。这些活性代谢物在体内可与蛋白质共价结合并引起显著的毒性，但其确切机制仍不清楚。我们研究计划的目标是设计新的方法来研究这些毒性相互作用。本研究的主要重点是设计新的策略，以进一步了解反应性代谢物与蛋白质的共价结合，使用基于小分子和蛋白质组学的质谱工具，

The main role of drug metabolism is to detoxify the body from xenobiotics, rendering them more polar and thus easily cleared. Some drugs, however, are bioactivated into reactive metabolites with the potential to covalently bind to proteins. This binding is considered to be an important cause of idiosyncratic drug reactions (IDR). As a result, the formation of reactive metabolites represents a significant liability for pharmaceutical compounds. These reactive metabolites can covalently bind to proteins in vivo and cause significant toxicity, however the exact mechanisms are still quite unclear. The goal of our research program is to design new methods to study these toxic interactions. The primary focus of this research is devising novel strategies to further understand reactive metabolite covalent binding to proteins using a combination of small molecule and proteomic-based mass spectrometry tools with the