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Revisiting Aldehyde Oxidase Mediated Metabolism in Drug-like Molecules: An Improved Computational Model

文献类型：期刊论文

作者Zhao, Jihui1,7; Cui, Rongrong1,3; Wang, Lihao1,6; Chen, Yingjia1; Fu, Zunyun1,3; Ding, Xiaoyu1; Cui, Chen1; Yang, Tianbiao1; Li, Xutong1; Xu, Yuan1,2
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2020-06-25
卷号63期号:12页码:6523-6537
ISSN号0022-2623
DOI10.1021/acs.jmedchem.9b01895
通讯作者Jiang, Hualiang(hljiang@simm.ac.cn) ; Zheng, Mingyue(myzheng@simm.ac.cn)
英文摘要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.
WOS关键词REACTIVITY ; PREDICTION ; INHIBITOR ; MECHANISM ; INSIGHTS ; SITE ; DISCOVERY ; POTENT
资助项目National Natural Science Foundation of China[81773634] ; National Science & Technology Major Project Key New Drug Creation and Manufacturing Program, China[2018ZX09711002] ; Molecular Signature-Based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12050201]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000545660500016
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/291851]  
专题新药研究国家重点实验室
通讯作者Jiang, Hualiang; Zheng, Mingyue
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
2.Shanghai EnnovaBio Pharmaceut Co Ltd, Shanghai 200120, Peoples R China
3.Nanjing Univ Chinese Med, Coll Pharm, Nanjing 210023, Peoples R China
4.ShanghaiTech Univ, Shanghai Inst Adv Immunochem Studies, Shanghai 200031, Peoples R China
5.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 200031, Peoples R China
6.Univ N Carolina, Gillings Sch Publ Hlth, Chapel Hill, NC 27599 USA
7.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
推荐引用方式
GB/T 7714		 Zhao, Jihui,Cui, Rongrong,Wang, Lihao,et al. Revisiting Aldehyde Oxidase Mediated Metabolism in Drug-like Molecules: An Improved Computational Model[J]. JOURNAL OF MEDICINAL CHEMISTRY,2020,63(12):6523-6537.
APA Zhao, Jihui.,Cui, Rongrong.,Wang, Lihao.,Chen, Yingjia.,Fu, Zunyun.,...&Zheng, Mingyue.(2020).Revisiting Aldehyde Oxidase Mediated Metabolism in Drug-like Molecules: An Improved Computational Model.JOURNAL OF MEDICINAL CHEMISTRY,63(12),6523-6537.
MLA Zhao, Jihui,et al."Revisiting Aldehyde Oxidase Mediated Metabolism in Drug-like Molecules: An Improved Computational Model".JOURNAL OF MEDICINAL CHEMISTRY 63.12(2020):6523-6537.

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来源：上海药物研究所

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