Revisiting Aldehyde Oxidase Mediated Metabolism in Drug-like Molecules: An Improved Computational Model.,Journal of Medicinal Chemistry

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Revisiting Aldehyde Oxidase Mediated Metabolism in Drug-like Molecules: An Improved Computational Model.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-03-19 , DOI: 10.1021/acs.jmedchem.9b01895
Jihui Zhao _{1,

2} , Rongrong Cui _{1,

3} , Lihao Wang ₄ , Yingjia Chen ₁ , Zunyun Fu _{1,

3} , Xiaoyu Ding ₁ , Chen Cui ₁ , Tianbiao Yang ₁ , Xutong Li ₁ , Yuan Xu ₅ , Kaixian Chen _{1,

3,

6} , Xiaomin Luo ₁ , Hualiang Jiang _{1,

3,

6} , Mingyue Zheng _{1,

2}

Affiliation

Aldehyde oxidase (AOX) is a drug metabolizing molybdo-flavoenzyme that has gained increasing attention because of contribution to the biotransformation in phase I metabolism of xenobiotics. Unfortunately, the intra- and interspecies variations in AOX activity and lack of reliable and predictive animal models make evaluation of AOX-catalyzed metabolism prone to be misleading. In this study, we developed an improved computational model integrating both atom-level and molecule-level features to predict whether a drug-like molecule is a potential human AOX (hAOX) substrate and to identify the corresponding sites of metabolism. Additionally, we combined the proposed computational strategy and in vitro experiments for evaluating the metabolic property of a series of epigenetic-related drug candidates still in the early stage of development. In summary, this study provides an improved strategy to evaluate the liability of molecules toward hAOX and offers useful information for accelerating the drug design and optimization stage.

中文翻译：

回顾醛氧化酶介导的药物样分子的代谢：改进的计算模型。

醛氧化酶（AOX）是一种代谢钼黄酮酶的药物，由于对异源生物I期代谢的生物转化做出了贡献，因此受到越来越多的关注。不幸的是，种内和种间AOX活性的变化以及缺乏可靠和可预测的动物模型使得对AOX催化的新陈代谢的评估容易产生误导。在这项研究中，我们开发了一种改进的计算模型，该模型结合了原子级和分子级功能，可以预测类药物分子是否是潜在的人类AOX（hAOX）底物，并确定相应的代谢位点。此外，我们结合了拟议的计算策略和体外实验，以评估仍处于开发初期的一系列表观遗传相关药物候选者的代谢特性。综上所述，

更新日期：2020-03-19

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