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Transfer learning enhanced graph neural network for aldehyde oxidase metabolism prediction and its experimental application

文献类型：期刊论文

作者Xiong, Jiacheng6,7; Cui, Rongrong6,7; Li, Zhaojun4,5; Zhang, Wei6,7; Zhang, Runze6,7; Fu, Zunyun6,7; Liu, Xiaohong4; Li, Zhenghao2,3; Chen, Kaixian6,7; Zheng, Mingyue1,6,7
刊名ACTA PHARMACEUTICA SINICA B
出版日期2024-02-01
卷号14期号:2页码:623-634
ISSN号2211-3835
关键词Drug metabolism Aldehyde oxidase Transfer learning Graph neural network Kinase inhibitor
DOI10.1016/j.apsb.2023.10.008
通讯作者Zheng, Mingyue(myzheng@simm.ac.cn)
英文摘要Aldehyde oxidase (AOX) is a molybdoenzyme that is primarily expressed in the liver and is involved in the metabolism of drugs and other xenobiotics. AOX-mediated metabolism can result in unexpected outcomes, such as the production of toxic metabolites and high metabolic clearance, which can lead to the clinical failure of novel therapeutic agents. Computational models can assist medicinal chemists in rapidly evaluating the AOX metabolic risk of compounds during the early phases of drug discovery and provide valuable clues for manipulating AOX-mediated metabolism liability. In this study, we developed a novel graph neural network called AOMP for predicting AOX-mediated metabolism. AOMP integrated the tasks of metabolic substrate/non-substrate classification and metabolic site prediction, while utilizing transfer learning from 13C nuclear magnetic resonance data to enhance its performance on both tasks. AOMP significantly outperformed the benchmark methods in both cross-validation and external testing. Using AOMP, we systematically assessed the AOX-mediated metabolism of common fragments in kinase inhibitors and successfully identified four new scaffolds with AOX metabolism liability, which were validated through in vitro experiments. Furthermore, for the convenience of the community, we established the first online service for AOX metabolism prediction based on AOMP, which is freely avail- able at https://aomp.alphama.com.cn. 2024 The Authors. Published by Elsevier B.V. on behalf of Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. This is an open access article under the CC BY -NC - ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
WOS关键词DRUG-DRUG INTERACTIONS ; BINDING ; INHIBITOR ; INSIGHTS
资助项目National Natural Science Foundation of China[T2225002] ; National Natural Science Foundation of China[82273855] ; Lingang Laboratory[LG202102-01-02] ; National Key Research and Development Program of China[KF-202301] ; National Key Research and Development Program of China[2022YFC3400504] ; State key laboratory of Pharmaceutical Biotechnology, Nanjing University, China[KF-202301]
WOS研究方向Pharmacology & Pharmacy
语种英语
出版者INST MATERIA MEDICA, CHINESE ACAD MEDICAL SCIENCES
WOS记录号WOS:001170588700001
源URL[http://119.78.100.183/handle/2S10ELR8/310109]  
专题中国科学院上海药物研究所
通讯作者Zheng, Mingyue
作者单位1.Nanjing Univ, State Key Lab Pharmaceut Biotechnol, Nanjing 210023, Peoples R China
2.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 200031, Peoples R China
3.ShanghaiTech Univ, Shanghai Inst Adv Immunochem Studies, Shanghai 200031, Peoples R China
4.Suzhou Alphama Biotechnol Co Ltd, AI Dept, Suzhou 215000, Peoples R China
5.Dezhou Univ, Coll Comp & Informat Engn, Dezhou 253023, Peoples R China
6.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
7.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Xiong, Jiacheng,Cui, Rongrong,Li, Zhaojun,et al. Transfer learning enhanced graph neural network for aldehyde oxidase metabolism prediction and its experimental application[J]. ACTA PHARMACEUTICA SINICA B,2024,14(2):623-634.
APA Xiong, Jiacheng.,Cui, Rongrong.,Li, Zhaojun.,Zhang, Wei.,Zhang, Runze.,...&Zheng, Mingyue.(2024).Transfer learning enhanced graph neural network for aldehyde oxidase metabolism prediction and its experimental application.ACTA PHARMACEUTICA SINICA B,14(2),623-634.
MLA Xiong, Jiacheng,et al."Transfer learning enhanced graph neural network for aldehyde oxidase metabolism prediction and its experimental application".ACTA PHARMACEUTICA SINICA B 14.2(2024):623-634.

入库方式： OAI收割

来源：上海药物研究所

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