The metabolism of CYP2C9 and CYP2C19 for gliclazide by homology modeling and docking study
The metabolism of CYP2C9 and CYP2C19 for gliclazide by homology modeling and docking study
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格列齐特CYP2C9和CYP2C19代谢同源建模及对接研究
DOI：
10.1016/j.ejmech.2008.04.015
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发表时间：
2009-02-01
影响因子：
6.7
通讯作者：
Zhong, Da-Fang
中科院分区：
文献类型：
--
作者：
Yao, Yuan;Han, Wei-Wei;Zhong, Da-Fang
采用同源建模技术，建立了CYP2C19的三维结构模型，并进行了分子力学和分子动力学模拟。通过Profile-3D和PROCHECK程序对改进后的模型进行了验证。在分子自动对接的帮助下，通过InsightII/Affacy程序将一个底物和两个抑制剂对接到了CYP2C19上。对接结果与文献报道的结果吻合较好，表明改进后的模型是可靠的。在此基础上，结合CYP2C19的精化模型和晶体结构，研究了它们在两条不同代谢途径中对格列齐特的代谢作用，结果表明两种酶在甲基羟化途径比6β-羟基化途径与格列齐特具有更有利的相互作用能和更强的亲和力。令人兴奋的是，在格列齐特的两条代谢途径中，都可以发现CYP2C9和CYP2C19的代谢过程中存在底物抑制现象。格列齐特对接在细胞色素P450_2C9和细胞色素P_2C_(19)的第二活性部位后，可以改变活性部位的构象，明显降低活性部位与酶的亲和力。这些结果与动力学实验结果吻合得很好。(C)2008年爱思唯尔·马森公司。版权所有。
With homology modeling techniques, a 3D structure model of CYP2C19 was built and refined with molecular mechanics and molecular dynamics simulations. The refined model was assessed to be reasonable by Profile-3D and PROCHECK programs. With the aid of the automatic molecular docking, one substrate and two inhibitors were docked to CYP2C19 by InsightII/Affinity program. The docking results, which are in well agreement with the reported results, demonstrate that the refined model of CYP2C19 is reliable. Then, with the refined model of CYP2C19 and the crystal structure of CYP2C9, the metabolisms of them for gliclazide in two different metabolic pathways were studied and the results show that both enzymes have more favorable interaction energies and stronger affinity with gliclazide in methylhydroxylation pathway than in 6 beta-hydroxylation pathway. It is exciting that substrate inhibition phenomenon can be found in metabolisms of CYP2C9 and CYP2C19 for gliclazide in two metabolic pathways. Gliclazide can change the conformation of the active sites and decrease obviously the affinities between gliclazide in the active site and enzymes when it is docked in the second active sites in CYP2C9 and CYP2C19. These results are in well agreement with the kinetic experimental results. (c) 2008 Elsevier Masson SAS. All rights reserved.