The recognition that only a small percentage of known human gene products are druggable using traditional modes of non-covalent ligand design, has led to a resurgence in targeted covalent inhibitors. Covalent inhibitors offer advantages over non-covalent inhibitors in engaging otherwise challenging targets. Reactive cysteine residues on proteins are a common target for covalent inhibitors, whereby the high nucleophilicity of the cysteine thiol under physiological conditions provides an ideal anchoring site for electrophilic small molecules. A chemical-proteomic platform, termed isoTOP-ABPP, allows for profiling cysteine reactivity in complex proteomes and is one of many techniques that can aid in two aspects of the covalent-inhibitor development process: (1) to identify functional cysteines that lead to modulation of protein activity through covalent modification; and, (2) to determine cellular targets and evaluate promiscuity of electrophilic fragments, small molecules, and natural products. Herein, we discuss recent advances in isoTOP-ABPP and potential applications of this technology in the drug-discovery pipeline.

中文翻译：

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反应性半胱氨酸谱用于药物发现。

使用传统的非共价配体设计模式，只有很少一部分已知的人类基因产物可药用，这一认识已导致靶向共价抑制剂的复苏。与非共价抑制剂相比，共价抑制剂在接合原本具有挑战性的靶标方面具有优势。蛋白质上的反应性半胱氨酸残基是共价抑制剂的常见目标，因此半胱氨酸硫醇在生理条件下的高亲核性为亲电子小分子提供了理想的锚定位点。一个化学蛋白质组学平台，称为isoTOP-ABPP，可以分析复杂蛋白质组中的半胱氨酸反应性，并且是可以在共价抑制剂开发过程的两个方面提供帮助的众多技术之一：（1）鉴定通过共价修饰导致蛋白质活性调节的功能性半胱氨酸；（2）确定细胞靶标并评估亲电片段，小分子和天然产物的混杂。本文中，我们讨论了isoTOP-ABPP的最新进展以及该技术在药物发现管道中的潜在应用。