Identification of cytochrome P450 2D6 and 2C9 substrates and inhibitors by QSAR analysis

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• 作者：Svava Ó ; sk Jó ; nsdó ; ttir ; ^{sojo@food.dtu.dk} ; Tine Ringsted ; Nikolai G. Nikolov ; Marianne Dybdahl ; Eva Bay Wedebye ; Jay R. Niemelä
• 关键词：CYP ; cytochrome P450 ; CYP2C9 ; cytochrome P450 subtype 2C9 ; CYP2D6 ; cytochrome P450 subtype 2D6 ; CYP1A2 ; cytochrome P450 subtype 1A2 ; CYP2C19 ; cytochrome P450 subtype 2C19 ; CYP3A4 ; cytochrome P450 subtype 3A4 ; PLR ; partial logistic regression ; PLS ; partial
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2012
• 期刊代码：9_09680896
• 类别：ch
• 出版时间：15 March, 2012
• 卷：20
• 期：6
• 页码：2042-2053
• 文件大小：472 K

摘要

This paper presents four new QSAR models for CYP2C9 and CYP2D6 substrate recognition and inhibitor identification based on human clinical data. The models were used to screen a large data set of environmental chemicals for CYP activity, and to analyze the frequency of CYP activity among these compounds. A large fraction of these chemicals were found to be CYP active, and thus potentially capable of affecting human physiology. 20%of the compounds within applicability domain of the models were predicted to be CYP2C9 substrates, and 17%to be inhibitors. The corresponding numbers for CYP2D6 were 9%and 21%. Where the majority of CYP2C9 active compounds were predicted to be both a substrate and an inhibitor at the same time, the CYP2D6 active compounds were primarily predicted to be only inhibitors. It was demonstrated that the models could identify compound classes with a high occurrence of specific CYP activity. An overrepresentation was seen for poly-aromatic hydrocarbons (group of procarcinogens) among CYP2C9 active and mutagenic compounds compared to CYP2C9 inactive and mutagenic compounds. The mutagenicity was predicted with a QSAR model based on Ames in vitro test data.