Mechanism of the Decrease in Catalytic Activity of Human Cytochrome P450 2C9 Polymorphic Variants Investigated by Computational Analysis
Mechanism of the Decrease in Catalytic Activity of Human Cytochrome P450 2C9 Polymorphic Variants Investigated by Computational Analysis
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DOI：
10.1002/jcc.21568
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发表时间：
2010-11-30
影响因子：
3
通讯作者：
Hoshino, Tyuji
中科院分区：
文献类型：
--
作者：
Sano, Eri;Li, Weihua;Hoshino, Tyuji
细胞色素 P450 (CYP) 深入参与包括药物在内的化学物质的代谢。因此，该酶的多态性已被广泛研究，以避免化疗中药物的不利副作用。在这项工作中，我们对 CYP 2C9 物种中三种典型多态性的酶活性降低机制进行了计算分析：*2、*3 和 *5。基于分子动力学模拟获得的平衡结构，比较了野生型和三种变体之间的结合袋体积和负责底物保持的氨基残基的波动。进行了进一步的对接模拟以评估结合袋容纳底物化学品的适当性。从结构的角度来看，每个多态性变体的酶促能力均低于野生型。 CYP2C9*2 中的 F-G 螺旋明显向外移位。 CYP2C9*3 中结合口袋的扩张，尤其是 F' 螺旋附近的空间，非常显着。在 CYP2C9*5 中观察到 K 螺旋和 β4 环之间的氢键消失。这些变体催化活性的降低可以通过结合袋的变形以及随之而来的底物化学物质的结合模式的变化来解释。该计算方法可有效预测 CYP 多态性变体的酶活性。这一预测将有助于先进的药物设计，因为计算可以预测个体药物功效的意外变化。 (C) 2010 Wiley Journals, Inc. J Comput Chem 31: 2746-2758, 2010
Cytochrome P450 (CYP) is deeply involved in the metabolism of chemicals including pharmaceuticals. Therefore, polymorphisms of this enzyme have been widely studied to avoid unfavorable side effects of drugs in chemotherapy. In this work, we performed computational analysis of the mechanism of the decrease in enzymatic activity for three typical polymorphisms in CYP 2C9 species: *2, *3, and *5. Based on the equilibrated structure obtained by molecular dynamics simulation, the volume of the binding pocket and the fluctuation of amino residues responsible for substrate holding were compared between the wild type and the three variants. Further docking simulation was carried out to evaluate the appropriateness of the binding pocket to accommodate substrate chemicals. Every polymorphic variant was suggested to be inferior to the wild type in enzymatic ability from the structural viewpoint. F-G helices were obviously displaced outward in CYP2C9*2. Expansion of the binding pocket, especially the space near F' helix, was remarkable in CYP2C9*3. Disappearance of the hydrogen bond between K helix and beta 4 loop was observed in CYP2C9*5. The reduction of catalytic activity of those variants can be explained from the deformation of the binding pocket and the consequent change in binding mode of substrate chemicals. The computational approach is effective for predicting the enzymatic activity of polymorphic variants of CYP. This prediction will be helpful for advanced drug design because calculations forecast unexpected change in drug efficacy for individuals. (C) 2010 Wiley Periodicals, Inc. J Comput Chem 31: 2746-2758, 2010