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学科主题: 物理化学
题名: Recent density functional theory model calculations of drug metabolism by cytochrome P450
作者: Li, Dongmei1, 2;  Wang, Yong1;  Han, Keli1
通讯作者: 韩克利
关键词: Density functional theory ;  Compound I ;  Hydrogen atom transfer ;  Two-state reactivity
刊名: COORDINATION CHEMISTRY REVIEWS
发表日期: 2012-06-01
DOI: 10.1016/j.ccr.2012.01.016
卷: 256, 期:11-12, 页:1137-1150
收录类别: SCI
文章类型: Review
部门归属: 11
项目归属: 1101
产权排名: 1,1
类目[WOS]: Chemistry, Inorganic & Nuclear
研究领域[WOS]: Chemistry
英文摘要: Cytochrome P450 (P450) enzymes are the major catalysts involved in the oxidative metabolism of most drugs, steroids, carcinogens, and other chemicals. They catalyze a variety of reactions and convert chemicals to potentially reactive products as well as make compounds less toxic. More than 75% of drugs in clinical use are metabolized by P450s. Understanding the mechanism of drug metabolism by P450, in particular the chemical process, is indispensable in the early phases of drug discovery process. In this review, we discuss our recent theoretical studies on the mechanism of some specific compounds catalyzed by P450. Density functional theory (DFT) is used as the quantum mechanical (QM) tool to explore the fundamental mechanism of these reactions. These DFT calculations provide structures, energies, and some other properties of transition states and intermediates and thus shed light on the electronic factors that govern the stability and reactivity. These theoretical studies provide a complementary insight to experiment and suggest some new features. DFT serves a powerful tool to explore the chemical mechanism of drug metabolism by P450. The revealed fundamental mechanism concerning how the enzyme catalyzes the drug metabolism, especially the transition state of the rate-determining reaction step, could provide a valuable mechanistic base for rational design of novel drugs. (C) 2012 Elsevier B.V. All rights reserved.
关键词[WOS]: C-H HYDROXYLATION ;  ISOTOPE EFFECT PROFILES ;  HUMAN LIVER-MICROSOMES ;  FUNDAMENTAL REACTION PATHWAYS ;  CATALYZED N-DEMETHYLATION ;  COMPOUND-I ;  SUBSTITUTED N,N-DIMETHYLANILINES ;  REBOUND MECHANISM ;  HYDROGEN ABSTRACTION ;  ELECTRONIC-STRUCTURE
语种: 英语
WOS记录号: WOS:000303787500005
Citation statistics: 
内容类型: 期刊论文
URI标识: http://cas-ir.dicp.ac.cn/handle/321008/117813
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, State Key Lab Mol React Dynam, Dalian 116023, Peoples R China
2.Nankai Univ, Coll Pharm, Tianjin 300071, Peoples R China

Recommended Citation:
Li, Dongmei,Wang, Yong,Han, Keli. Recent density functional theory model calculations of drug metabolism by cytochrome P450[J]. COORDINATION CHEMISTRY REVIEWS,2012,256(11-12):1137-1150.
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