Trends in predicted chemoselectivity of cytochrome P450 oxidation: B3LYP barrier heights for epoxidation and hydroxylation reactions

Patrik Rydberg; Richard Lonsdale; Jeremy N Harvey; Adrian J Mulholland; Lars Olsen

doi:10.1016/j.jmgm.2014.06.002

Trends in predicted chemoselectivity of cytochrome P450 oxidation: B3LYP barrier heights for epoxidation and hydroxylation reactions

Patrik Rydberg, Richard Lonsdale, Jeremy N Harvey, Adrian J Mulholland, Lars Olsen

17 Citationer (Scopus)

Abstract

Prediction of epoxide formation in drug metabolism is a difficult but important task, as epoxide formation is linked to drug toxicity. A comparison of the energy barriers for cytochrome P450 mediated epoxidation of alkenes to the barriers for the hydroxylation of an aliphatic carbon atom next to a double bond has been performed using B3LYP and B3LYP-D3. Relevant experimental data on oxidation selectivity has also been assessed. The results show that density functional theory, when using B3LYP-D3, does well in reproducing the experimental trends. Considering that the comparison involves chemical steps with quite different features this is remarkable. We also find that B3LYP consistently underestimates the hydrogen abstraction barriers relative to the epoxidation barriers, and that including a dispersion correction reduces this problem.

Originalsprog	Engelsk
Tidsskrift	Journal of Molecular Graphics and Modelling
Vol/bind	52
Sider (fra-til)	30-5
Antal sider	6
ISSN	1093-3263
DOI	https://doi.org/10.1016/j.jmgm.2014.06.002
Status	Udgivet - jul. 2014

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10.1016/j.jmgm.2014.06.002

Citationsformater

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title = "Trends in predicted chemoselectivity of cytochrome P450 oxidation: B3LYP barrier heights for epoxidation and hydroxylation reactions",

abstract = "Prediction of epoxide formation in drug metabolism is a difficult but important task, as epoxide formation is linked to drug toxicity. A comparison of the energy barriers for cytochrome P450 mediated epoxidation of alkenes to the barriers for the hydroxylation of an aliphatic carbon atom next to a double bond has been performed using B3LYP and B3LYP-D3. Relevant experimental data on oxidation selectivity has also been assessed. The results show that density functional theory, when using B3LYP-D3, does well in reproducing the experimental trends. Considering that the comparison involves chemical steps with quite different features this is remarkable. We also find that B3LYP consistently underestimates the hydrogen abstraction barriers relative to the epoxidation barriers, and that including a dispersion correction reduces this problem.",

author = "Patrik Rydberg and Richard Lonsdale and Harvey, {Jeremy N} and Mulholland, {Adrian J} and Lars Olsen",

note = "Copyright {\textcopyright} 2014. Published by Elsevier Inc.",

year = "2014",

month = jul,

doi = "10.1016/j.jmgm.2014.06.002",

language = "English",

volume = "52",

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TY - JOUR

T1 - Trends in predicted chemoselectivity of cytochrome P450 oxidation

T2 - B3LYP barrier heights for epoxidation and hydroxylation reactions

AU - Rydberg, Patrik

AU - Lonsdale, Richard

AU - Harvey, Jeremy N

AU - Mulholland, Adrian J

AU - Olsen, Lars

PY - 2014/7

Y1 - 2014/7

N2 - Prediction of epoxide formation in drug metabolism is a difficult but important task, as epoxide formation is linked to drug toxicity. A comparison of the energy barriers for cytochrome P450 mediated epoxidation of alkenes to the barriers for the hydroxylation of an aliphatic carbon atom next to a double bond has been performed using B3LYP and B3LYP-D3. Relevant experimental data on oxidation selectivity has also been assessed. The results show that density functional theory, when using B3LYP-D3, does well in reproducing the experimental trends. Considering that the comparison involves chemical steps with quite different features this is remarkable. We also find that B3LYP consistently underestimates the hydrogen abstraction barriers relative to the epoxidation barriers, and that including a dispersion correction reduces this problem.

AB - Prediction of epoxide formation in drug metabolism is a difficult but important task, as epoxide formation is linked to drug toxicity. A comparison of the energy barriers for cytochrome P450 mediated epoxidation of alkenes to the barriers for the hydroxylation of an aliphatic carbon atom next to a double bond has been performed using B3LYP and B3LYP-D3. Relevant experimental data on oxidation selectivity has also been assessed. The results show that density functional theory, when using B3LYP-D3, does well in reproducing the experimental trends. Considering that the comparison involves chemical steps with quite different features this is remarkable. We also find that B3LYP consistently underestimates the hydrogen abstraction barriers relative to the epoxidation barriers, and that including a dispersion correction reduces this problem.

U2 - 10.1016/j.jmgm.2014.06.002

DO - 10.1016/j.jmgm.2014.06.002

M3 - Journal article

C2 - 25000094

SN - 1093-3263

VL - 52

SP - 30

EP - 35

JO - Journal of Molecular Graphics and Modelling

JF - Journal of Molecular Graphics and Modelling

ER -

Trends in predicted chemoselectivity of cytochrome P450 oxidation: B3LYP barrier heights for epoxidation and hydroxylation reactions

Abstract

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