GLORY: Generator of the Structures of Likely Cytochrome P450 Metabolites Based on Predicted Sites of Metabolism
GLORY: Generator of the Structures of Likely Cytochrome P450 Metabolites Based on Predicted Sites of Metabolism
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DOI：
10.3389/fchem.2019.00402
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发表时间：
2019-06-12
影响因子：
5.5
通讯作者：
Kirchmair, Johannes
中科院分区：
文献类型：
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作者：
Kops, Christina de Bruyn;Stork, Conrad;Kirchmair, Johannes
外源代谢的计算预测可以为指导药物、化妆品、农用化学品和其他化学实体的开发提供有价值的信息。我们之前开发了 FAME 2，这是一种预测代谢位点 (SoM) 的有效工具。在这项工作中，我们重点关注代谢物的化学结构的预测，特别是外源物质的代谢物。为此，我们开发了一种新工具 GLORY，它将 SoM 预测与 FAME 2 以及细胞色素 P450 酶家族介导的代谢反应的新规则集合相结合。 GLORY有两种模式：MaxEfficiency和MaxCoverage。对于 MaxEfficiency 模式，探索了使用预测的 SoM 来限制分子中可以应用反应规则的位置。对于 MaxCoverage 模式，预测的 SoM 概率被用来为预测的代谢物开发新的评分方法。通过这种评分方法，GLORY 的召回率达到 0.83，并且可以在新的手动策划的测试集中预测 76% 的分子的前三名中的至少一种已知代谢物。 GLORY 可作为网络服务器免费使用，网址为 https://acm.zbh.uni-hamburg.de/glory/，数据集和反应规则在补充材料中提供。
Computational prediction of xenobiotic metabolism can provide valuable information to guide the development of drugs, cosmetics, agrochemicals, and other chemical entities. We have previously developed FAME 2, an effective tool for predicting sites of metabolism (SoMs). In this work, we focus on the prediction of the chemical structures of metabolites, in particular metabolites of xenobiotics. To this end, we have developed a new tool, GLORY, which combines SoM prediction with FAME 2 and a new collection of rules for metabolic reactions mediated by the cytochrome P450 enzyme family. GLORY has two modes: MaxEfficiency and MaxCoverage. For MaxEfficiency mode, the use of predicted SoMs to restrict the locations in the molecule at which the reaction rules could be applied was explored. For MaxCoverage mode, the predicted SoM probabilities were instead used to develop a new scoring approach for the predicted metabolites. With this scoring approach, GLORY achieves a recall of 0.83 and can predict at least one known metabolite within the top three ranked positions for 76% of the molecules of a new, manually curated test set. GLORY is freely available as a web server at https:// acm.zbh.uni-hamburg.de/glory/, and the datasets and reaction rules are provided in the Supplementary Material.