Aldehyde Oxidase Mediated Metabolism in Drug-like Molecules: A Combined Computational and Experimental Study,Journal of Medicinal Chemistry

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Aldehyde Oxidase Mediated Metabolism in Drug-like Molecules: A Combined Computational and Experimental Study
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-03-16 00:00:00 , DOI: 10.1021/acs.jmedchem.7b00019
Yuan Xu _{1,

2} , Liang Li ₁ , Yulan Wang _{1,

2} , Jing Xing _{1,

2} , Lei Zhou _{1,

2} , Dafang Zhong ₁ , Xiaomin Luo ₁ , Hualiang Jiang ₁ , Kaixian Chen ₁ , Mingyue Zheng ₁ , Pan Deng ₁ , Xiaoyan Chen ₁

Affiliation

Aldehyde oxidase (AOX) is an important drug-metabolizing enzyme. However, the current in vitro models for evaluating AOX metabolism are sometimes misleading, and preclinical animal models generally fail to predict human AOX-mediated metabolism. In this study, we report a combined computational and experimental investigation of drug-like molecules that are potential aldehyde oxidase substrates, of which multiple sites of metabolism (SOMs) mediated by AOX and their preferences for the reaction can be unambiguously identified. In addition, the proposed strategy was used to evaluate the metabolism of newly designed c-Met inhibitors, and a success switch-off of AOX metabolism was observed. Overall, this study provide useful information to guide lead optimization and drug discovery based on AOX-mediated metabolism.

中文翻译：

醛氧化酶介导的类药物分子的代谢：计算和实验相结合的研究。

醛氧化酶（AOX）是一种重要的药物代谢酶。但是，当前用于评估AOX代谢的体外模型有时会产生误导，临床前动物模型通常无法预测人AOX介导的代谢。在这项研究中，我们报告了作为潜在的醛氧化酶底物的类药物分子的组合计算和实验研究，可以明确地确定由AOX介导的多个代谢位点（SOM）及其对反应的偏好。此外，所提出的策略用于评估新设计的c-Met抑制剂的代谢，并观察到AOX代谢成功关闭。总的来说，这项研究提供了有用的信息，以指导基于AOX介导的代谢的前导优化和药物发现。

更新日期：2017-03-16

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