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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Homology modeling and molecular dynamics of CYP1A1 and CYP2B1 to explore the metabolism of aryl derivatives by docking and experimental assays.
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Homology modeling and molecular dynamics of CYP1A1 and CYP2B1 to explore the metabolism of aryl derivatives by docking and experimental assays.

机译：CYP1A1和CYP2B1的同源性建模与分子动力学通过对接和实验测定来探讨芳基衍生物的代谢。

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Since many drugs are metabolized by cytochrome P450 (CYP450), biotransformation studies using these enzymes are valuable in drug development. In this work, the biotransformation by CYP1A1 and CYP2B1 of two acetylcholinesterase (AChE) inhibitors, 4-(4'-hydroxy-phenylamino)-4-oxo propanoic acid (A) and 1H-pyrrolidine-1-(4'-hydroxy-phenyl)-2,5-dione (B), was investigated through docking and molecular dynamics (MD) simulations and by experimental methods using rat liver microsomes pretreated with beta-naphthoflavone and phenobarbital (CYP1A1 and CYP2B1 inducers, respectively). The target proteins were initially built by homology modeling, and the resulting three-dimensional structures were refined by MD to obtain fifteen snapshots of each P450 isoform. These snapshots were used to dock compounds A and B as well as the reference compound acetaminophen (APAP). We confirmed that APAP produces a toxic intermediate (N-acetyl-p-benzoquinone imine) upon interaction of its amide group with the heme iron of CYP1A1. However, neither A nor B presented this kind of interaction within any snapshot with CYP1A1. On the other hand, when APAP, A and B were docked on CYP2B1, their hydroxyl group was located near the heme iron on the snapshot at 3.5 ns. Furthermore, B maintained the same position on all snapshots of this isoform. Therefore, theoretical results suggests that A and B do not generate toxic metabolites. These data were supported by HPLC analysis showing only one metabolite from A and B, which was identified by GC-MS as the hydroxylated product. Altogether, our results suggest that neither test compound is toxic.
机译：由于许多药物由细胞色素P450（CYP450）代谢，因此使用这些酶的生物转化研究在药物发育中是有价值的。在这项工作中，通过CYP1A1和两种乙酰胆碱酯酶（ACHE）抑制剂的CYP1A1和CYP2B1的生物转化，4-（4'-羟基 - 苯基氨基）-4-氧代丙酸（A）和1H-吡咯烷-1-（4'-羟基 - 通过对接和分子动力学（MD）模拟研究-2,5-二酮（B），并通过使用β-萘酚和苯巴比妥（CYP1A1和CYP2B1诱导剂）进行预处理的大鼠肝微粒体的实验方法研究。靶蛋白最初由同源性建模构建，并通过MD改进所得到的三维结构，得到每种P450同种型的十五个快照。这些快照用于停靠化合物A和B以及参考化合物乙酰氨基酚（APAP）。我们确认APAP在其酰胺基与CYP1A1的血红素熨斗相互作用时产生有毒中间体（N-乙酰基-P-苯醌型亚胺）。但是，NOR BOR B NOR B与CYP1A1的任何快照呈现这种交互。另一方面，当APAP，A和B停靠在CYP2B1上时，它们的羟基位于3.5ns的快照上的血红素熨斗附近。此外，B在这种同种型的所有快照上保持相同的位置。因此，理论结果表明A和B不会产生有毒代谢物。通过HPLC分析支持这些数据，仅显示A和B的一个代谢物，其通过GC-MS作为羟基化产物鉴定。完全，我们的结果表明，两种测试化合物都没有毒性。

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