Enzyme-Inhibitor Interactions and a Simple, Rapid Method for Determining Inhibition Modality
Enzyme-Inhibitor Interactions and a Simple, Rapid Method for Determining Inhibition Modality
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DOI：
10.1177/2472555219829898
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发表时间：
2019-06-01
期刊：
影响因子：
3.1
通讯作者：
Copeland, Robert A.
中科院分区：
文献类型：
--
作者：
Buker, Shane M.;Boriack-Sjodin, P. Ann;Copeland, Robert A.
现代化学生物学和药物发现越来越注重发现以特定方式与酶靶标相互作用的抑制分子，如变构或正构结合。因此，人们越来越有兴趣评估高通量多样性筛选中的命中化合物，以确定它们与靶标的相互作用模式。在这项工作中，常见的抑制方式进行了回顾和澄清。还回顾了底物浓度相对于底物K-M对每种常见抑制方式的影响。随着底物浓度的增加，IC50的变化模式被证明是特定抑制模式的诊断。因此，建议将IC_(50)作为比值[S]/K-M的函数重新绘制，作为一种简单、快速地评估抑制方式的方法。最后，对利用IC50曲线确定抑制通道的理想实验条件提出了具体的建议。
Contemporary chemical biology and drug discovery are increasingly focused on the discovery of inhibitory molecules that interact with enzyme targets in specific ways, such as allosteric or orthosteric binding. Hence, there is increasing interest in evaluating hit compounds from high-throughput diversity screening to determine their mode of interaction with the target. In this work, the common inhibition modalities are reviewed and clarified. The impact of substrate concentration, relative to substrate K-M, for each common inhibition modality is also reviewed. The pattern of changes in IC50 that accompany increasing substrate concentration are shown to be diagnostic of specific inhibition modalities. Thus, replots of IC50 as a function of the ratio [S]/K-M are recommended as a simple and rapid means of assessing inhibition modality. Finally, specific recommendations are offered for ideal experimental conditions for the determination of inhibition modality through the use of IC50 replots.