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

Publication: Research - peer-reviewJournal article – Annual report year: 2012

Standard

Harvard

APA

CBE

MLA

Vancouver

Author

Bibtex

@article{bef15ed1160146f183de1c685e630215,
title = "Identification of cytochrome P450 2D6 and 2C9 substrates and inhibitors by QSAR analysis",
publisher = "Pergamon",
author = "Jónsdóttir, {Svava Ósk} and Tine Ringsted and Nikolov, {Nikolai G.} and Marianne Dybdahl and Wedebye, {Eva Bay} and Niemelä, {Jay R.}",
year = "2012",
doi = "10.1016/j.bmc.2012.01.049",
volume = "20",
number = "6",
pages = "2042--2053",
journal = "Bioorganic & Medicinal Chemistry",
issn = "0968-0896",

}

RIS

TY - JOUR

T1 - Identification of cytochrome P450 2D6 and 2C9 substrates and inhibitors by QSAR analysis

A1 - Jónsdóttir,Svava Ósk

A1 - Ringsted,Tine

A1 - Nikolov,Nikolai G.

A1 - Dybdahl,Marianne

A1 - Wedebye,Eva Bay

A1 - Niemelä,Jay R.

AU - Jónsdóttir,Svava Ósk

AU - Ringsted,Tine

AU - Nikolov,Nikolai G.

AU - Dybdahl,Marianne

AU - Wedebye,Eva Bay

AU - Niemelä,Jay R.

PB - Pergamon

PY - 2012

Y1 - 2012

N2 - 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.

AB - 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.

KW - QSAR

KW - CYP2D6

KW - CYP2C9

KW - Substrate

KW - Inhibitor

KW - Procarcinogens

U2 - 10.1016/j.bmc.2012.01.049

DO - 10.1016/j.bmc.2012.01.049

JO - Bioorganic & Medicinal Chemistry

JF - Bioorganic & Medicinal Chemistry

SN - 0968-0896

IS - 6

VL - 20

SP - 2042

EP - 2053

ER -