细胞色素 P450 代谢 II 型结合化合物的动力学机制：支持直接还原的证据。
The kinetic mechanism for cytochrome P450 metabolism of type II binding compounds: evidence supporting direct reduction.
机构信息
Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., Seattle, WA 98119, United States.
出版信息
Arch Biochem Biophys. 2011 Jul;511(1-2):69-79. doi: 10.1016/j.abb.2011.04.008. Epub 2011 Apr 21.
Abstract
The metabolic stability of a drug is an important property that should be optimized during drug design and development. Nitrogen incorporation is hypothesized to increase the stability by coordination of nitrogen to the heme iron of cytochrome P450, a binding mode that is referred to as type II binding. However, we noticed that the type II binding compound 1 has less metabolic stability at sub-saturating conditions than a closely related type I binding compound 3. Three kinetic models will be presented for type II binder metabolism; (1) Dead-end type II binding, (2) a rapid equilibrium between type I and II binding modes before reduction, and (3) a direct reduction of the type II coordinated heme. Data will be presented on reduction rates of iron, the off rates of substrate (using surface plasmon resonance) and the catalytic rate constants. These data argue against the dead-end, and rapid equilibrium models, leaving the direct reduction kinetic mechanism for metabolism of the type II binding compound 1.
摘要
药物的代谢稳定性是药物设计和开发过程中应优化的一个重要性质。氮原子的掺入被假设通过氮与细胞色素 P450 的血红素铁的配位来增加稳定性，这种结合模式被称为 II 型结合。然而，我们注意到，在亚饱和条件下，与密切相关的 I 型结合化合物 3 相比，II 型结合化合物 1 的代谢稳定性较低。将提出三种用于 II 型结合物代谢的动力学模型；（1）末端 II 型结合，（2）还原前 I 型和 II 型结合模式之间的快速平衡，以及（3）II 型配位血红素的直接还原。将介绍铁的还原速率、底物的离解速率（使用表面等离子体共振）和催化速率常数的数据。这些数据反对末端和快速平衡模型，为 I 型结合化合物 1 的代谢留下了直接还原动力学机制。
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