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首页> 外文期刊>The journal of physical chemistry, A. Molecules, spectroscopy, kinetics, environment, & general theory >How Do Azoles Inhibit Cytochrome P450 Enzymes? A Density Functional Study
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How Do Azoles Inhibit Cytochrome P450 Enzymes? A Density Functional Study

机译：Azoles如何抑制细胞色素P450酶？密度泛函研究

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To examine how azole inhibitors interact with the heme active site of the cytochrome P450 enzymes, we have performed a series of density functional theory studies on azole binding. These are the first density functional studies on azole interactions with a heme center and give fundamental insight into how azoles inhibit the catalytic function of P450 enzymes. Since azoles come in many varieties, we tested three typical azole motifs representing a broad range of azole and azole-type inhibitors: methylimidazolate, methyltriazolate, and pyridine. These structural motifs represent typical azoles, such as econazole, fluconazole, and metyrapone. The calculations show that azole binding is a stepwise mechanism whereby first the water molecule from the resting state of P450 is released from the sixth binding site of the heme to create a pentacoordinated active site followed by coordination of the azole nitrogen to the heme iron. This process leads to the breaking of a hydrogen bond between the resting state water molecule and the approaching inhibitor molecule. Although, formally, the water molecule is released in the first step of the reaction mechanism and a pentacoordinated heme is created, this does not lead to an observed spin state crossing. Thus, we show that release of a water molecule from the resting state of P450 enzymes to create a pentacoordinated heme will lead to a doublet to quartet spin state crossing at an Fe-OH2 distance of approximately 3.0 angstrom, while the azole substitution process takes place at shorter distances. Azoles bind heme with significantly stronger binding energies than a water molecule, so that these inhibitors block the catalytic cycle of the enzyme and prevent oxygen binding and the catalysis of substrate oxidation. Perturbations within the active site (e.g., a polarized environment) have little effect on the relative energies of azole binding. Studies with an extra hydrogen-bonded ethanol molecule in the model, mimicking the active site of the CYP121 P450, show that the resting state and azole binding structures are close in energy, which may lead to chemical equilibrium between the two structures, as indeed observed with recent protein structural studies that have demonstrated two distinct azole binding mechanisms to P450 heme.
机译：为了检查唑类抑制剂如何与细胞色素P450酶的血红素活性位点相互作用，我们对唑类结合进行了一系列密度泛函理论研究。这些是关于吡咯与血红素中心相互作用的第一个密度泛函研究，对吡咯如何抑制P450酶的催化功能提供了基本的见识。由于唑类化合物种类繁多，因此我们测试了代表多种唑类和唑类抑制剂的三种典型的唑基序：甲基咪唑酯，三唑甲基酯和吡啶。这些结构基序代表典型的唑类，例如益康唑，氟康唑和甲吡酮。计算表明，吡咯结合是一种逐步的机制，其中首先从静止状态的P450水分子从血红素的第六个结合位点释放出来，形成五配位的活性位点，然后将吡咯氮与血红素铁配位。该过程导致在静止状态水分子和接近的抑制剂分子之间的氢键断裂。尽管从形式上讲，水分子在反应机理的第一步中被释放，并生成了五配位的血红素，但这并没有导致观察到的自旋态交叉。因此，我们表明从静止状态的P450酶释放水分子以生成五配位的血红素将导致在大约3.0埃的Fe-OH2距离处发生从双态到四重态的自旋态交叉，同时发生了吡咯取代过程。在较短的距离。偶氮化合物与血红素的结合能比水分子强得多，因此这些抑制剂可阻止酶的催化循环并防止氧结合和底物氧化的催化作用。活性位点（例如，极化环境）内的扰动对唑结合的相对能量影响很小。在模型中模拟CYP121 P450的活性位点时，使用额外的氢键合乙醇分子进行的研究表明，静息态和吡咯结合结构的能量接近，这可能导致这两个结构之间的化学平衡最近的蛋白质结构研究表明，P450血红素具有两种独特的唑结合机制。

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