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

Svava Ósk Jónsdóttir, Tine Ringsted, Nikolai G. Nikolov, Marianne Dybdahl, Eva Bay Wedebye, Jay R. Niemelä

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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.
Original languageEnglish
JournalBioorganic & Medicinal Chemistry
Issue number6
Pages (from-to)2042-2053
Publication statusPublished - 2012


  • QSAR
  • CYP2D6
  • CYP2C9
  • Substrate
  • Inhibitor
  • Procarcinogens


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