Rational Optimization of Mechanism-Based Inhibitors through Determination of the Microscopic Rate Constants of Inactivation,Journal of the American Chemical Society

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Rational Optimization of Mechanism-Based Inhibitors through Determination of the Microscopic Rate Constants of Inactivation
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2017-05-16 00:00:00 , DOI: 10.1021/jacs.7b00962
Carter G. Eiden ₁ , Kimberly M. Maize ₁ , Barry C. Finzel ₁ , John D. Lipscomb ₂ , Courtney C. Aldrich ₁

Affiliation

Mechanism-based inhibitors (MBIs) are widely employed in chemistry, biology, and medicine because of their exquisite specificity and sustained duration of inhibition. Optimization of MBIs is complicated because of time-dependent inhibition resulting from multistep inactivation mechanisms. The global kinetic parameters k_inact and K_I have been used to characterize MBIs, but they provide far less information than is commonly assumed, as shown by derivation and simulation of these parameters. We illustrate an alternative and more rigorous approach for MBI characterization through determination of the individual microscopic rate constants. Kinetic analysis revealed the rate-limiting step of inactivation of the PLP-dependent enzyme BioA by dihydro-(1,4)-pyridone 1. This knowledge was subsequently applied to rationally design a second-generation inhibitor scaffold with a nearly optimal maximum inactivation rate (0.48 min^–1).

中文翻译：

通过确定失活的微观速率常数来合理优化基于机制的抑制剂

基于机理的抑制剂（MBI）由于其精湛的特异性和持续的抑制持续时间而广泛用于化学，生物学和医学领域。MBI的优化非常复杂，因为多步失活机制会导致时间依赖性抑制。全局动力学参数k _inact和K _I已用于表征MBI，但与通常假定的信息相比，它们提供的信息要少得多，如这些参数的推导和仿真所示。我们通过确定各个微观速率常数，说明了MBI表征的另一种更严格的方法。动力学分析揭示了二氢-（1,4）-吡啶酮使PLP依赖性酶BioA失活的限速步骤1。该知识随后被应用于合理设计具有几乎最佳最大失活速率（0.48 min ^–1）的第二代抑制剂支架。

更新日期：2017-05-19

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