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题名: A Mechanism-Based Model for the Prediction of the Metabolic Sites of Steroids Mediated by Cytochrome P450 3A4
作者: Dai, Zi-Ru1, 2;  Ai, Chun-Zhi1;  Ge, Guang-Bo1;  He, Yu-Qi1;  Wu, Jing-Jing1;  Wang, Jia-Yue1;  Man, Hui-Zi1;  Jia, Yan1, 2;  Yang, Ling1
关键词: CYP3A4 ;  steroids ;  metabolic site ;  mechanism-based prediction ;  activation energy
刊名: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
发表日期: 2015-07-01
DOI: 10.3390/ijms160714677
卷: 16, 期:7, 页:14677-14694
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology ;  Life Sciences & Biomedicine ;  Physical Sciences
类目[WOS]: Biochemistry & Molecular Biology ;  Chemistry, Multidisciplinary
研究领域[WOS]: Biochemistry & Molecular Biology ;  Chemistry
英文摘要: Early prediction of xenobiotic metabolism is essential for drug discovery and development. As the most important human drug-metabolizing enzyme, cytochrome P450 3A4 has a large active cavity and metabolizes a broad spectrum of substrates. The poor substrate specificity of CYP3A4 makes it a huge challenge to predict the metabolic site(s) on its substrates. This study aimed to develop a mechanism-based prediction model based on two key parameters, including the binding conformation and the reaction activity of ligands, which could reveal the process of real metabolic reaction(s) and the site(s) of modification. The newly established model was applied to predict the metabolic site(s) of steroids; a class of CYP3A4-preferred substrates. 38 steroids and 12 non-steroids were randomly divided into training and test sets. Two major metabolic reactions, including aliphatic hydroxylation and N-dealkylation, were involved in this study. At least one of the top three predicted metabolic sites was validated by the experimental data. The overall accuracy for the training and test were 82.14% and 86.36%, respectively. In summary, a mechanism-based prediction model was established for the first time, which could be used to predict the metabolic site(s) of CYP3A4 on steroids with high predictive accuracy.
关键词[WOS]: HUMAN LIVER-MICROSOMES ;  P450-MEDIATED DRUG-METABOLISM ;  PHASE-I METABOLISM ;  ACTIVE-SITE ;  COMPUTATIONAL PREDICTION ;  CRYSTAL-STRUCTURES ;  P450 ;  BINDING ;  HYDROXYLATION ;  ENZYMES
语种: 英语
WOS记录号: WOS:000359900100025
Citation statistics: 
内容类型: 期刊论文
URI标识: http://cas-ir.dicp.ac.cn/handle/321008/146469
Appears in Collections:中国科学院大连化学物理研究所_期刊论文

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作者单位: 1.Chinese Acad Sci, Dalian Inst Chem Phys, Dalian 116023, Peoples R China
2.Chinese Acad Sci, Grad Sch, Beijing 100049, Peoples R China

Recommended Citation:
Dai, Zi-Ru,Ai, Chun-Zhi,Ge, Guang-Bo,et al. A Mechanism-Based Model for the Prediction of the Metabolic Sites of Steroids Mediated by Cytochrome P450 3A4[J]. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES,2015,16(7):14677-14694.
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