Revisiting Aldehyde Oxidase Mediated Metabolism in Drug-like Molecules: An Improved Computational Model
Revisiting Aldehyde Oxidase Mediated Metabolism in Drug-like Molecules: An Improved Computational Model
复制标题
重新审视药物样分子中醛氧化酶介导的代谢：改进的计算模型
DOI：
10.1021/acs.jmedchem.9b01895
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发表时间：
2020
影响因子：
7.3
通讯作者：
Zheng M.
中科院分区：
文献类型：
--
作者：
Zhao J.;Cui R.;Wang L.;Chen Y.;Fu Z.;Ding X.;Cui C.;Yang T.;Li X.;Xu Y.;Chen K.;Luo X.;Jiang H.;Zheng M.
醛氧化酶（AOX）是一种重要的药物代谢酶，因其在异源物质代谢的I相过程中起重要作用而受到广泛关注。不幸的是，AOX活性的种内和种间变化以及缺乏可靠和预测的动物模型使得对AOX催化的代谢的评价容易产生误导。在这项研究中，我们开发了一个改进的计算模型，结合原子水平和分子水平的功能，预测是否药物样分子是一个潜在的人类AOX（hAOX）底物，并确定相应的代谢位点。此外，我们结合所提出的计算策略和体外实验，用于评估仍处于早期开发阶段的一系列表观遗传相关候选药物的代谢特性。总之，本研究提供了一种改进的策略来评估分子对hAOX的易感性，并为加速药物设计和优化阶段提供了有用的信息。
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.