Density functional theory study on the formation of reactive benzoquinone imines by hydrogen abstraction

Research output: Contribution to journalJournal articleResearchpeer-review

Standard

Density functional theory study on the formation of reactive benzoquinone imines by hydrogen abstraction. / Leth, Rasmus; Rydberg, Patrik; Jørgensen, Flemming Steen; Olsen, Lars.

In: Journal of Chemical Information and Modeling, Vol. 55, No. 3, 23.03.2015, p. 660-6.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Leth, R, Rydberg, P, Jørgensen, FS & Olsen, L 2015, 'Density functional theory study on the formation of reactive benzoquinone imines by hydrogen abstraction', Journal of Chemical Information and Modeling, vol. 55, no. 3, pp. 660-6. https://doi.org/10.1021/ci500653b

APA

Leth, R., Rydberg, P., Jørgensen, F. S., & Olsen, L. (2015). Density functional theory study on the formation of reactive benzoquinone imines by hydrogen abstraction. Journal of Chemical Information and Modeling, 55(3), 660-6. https://doi.org/10.1021/ci500653b

Vancouver

Leth R, Rydberg P, Jørgensen FS, Olsen L. Density functional theory study on the formation of reactive benzoquinone imines by hydrogen abstraction. Journal of Chemical Information and Modeling. 2015 Mar 23;55(3):660-6. https://doi.org/10.1021/ci500653b

Author

Leth, Rasmus ; Rydberg, Patrik ; Jørgensen, Flemming Steen ; Olsen, Lars. / Density functional theory study on the formation of reactive benzoquinone imines by hydrogen abstraction. In: Journal of Chemical Information and Modeling. 2015 ; Vol. 55, No. 3. pp. 660-6.

Bibtex

@article{44ee5908743745f49a2d7f07ed7bea23,
title = "Density functional theory study on the formation of reactive benzoquinone imines by hydrogen abstraction",
abstract = "Many drug compounds are oxidized by cytochrome P450 (CYP) enzymes to form reactive metabolites. This study presents density functional theory calculations of the CYP-mediated metabolism of acetaminophen and a series of related compounds that can form reactive metabolites by hydrogen abstraction. The substitution pattern affects the activation barrier for hydrogen abstraction by up to 30 kJ/mol. A correlation (R(2) = 0.72) between the transition-state energies and the corresponding substrate radical energies has been established. Using this correlation is significantly less time-demanding than using the porphyrin model to determine the activation energies. We have used this correlation on monosubstituted phenols to rationalize the effect of the various substituents in the drug compounds. In addition to facilitating a chemical interpretation, the approach is sufficiently fast and reliable to be used as an in silico method in the design of new compounds with improved metabolic stability.",
author = "Rasmus Leth and Patrik Rydberg and J{\o}rgensen, {Flemming Steen} and Lars Olsen",
year = "2015",
month = "3",
day = "23",
doi = "10.1021/ci500653b",
language = "English",
volume = "55",
pages = "660--6",
journal = "Journal of Chemical Information and Modeling",
issn = "1549-9596",
publisher = "American Chemical Society",
number = "3",

}

RIS

TY - JOUR

T1 - Density functional theory study on the formation of reactive benzoquinone imines by hydrogen abstraction

AU - Leth, Rasmus

AU - Rydberg, Patrik

AU - Jørgensen, Flemming Steen

AU - Olsen, Lars

PY - 2015/3/23

Y1 - 2015/3/23

N2 - Many drug compounds are oxidized by cytochrome P450 (CYP) enzymes to form reactive metabolites. This study presents density functional theory calculations of the CYP-mediated metabolism of acetaminophen and a series of related compounds that can form reactive metabolites by hydrogen abstraction. The substitution pattern affects the activation barrier for hydrogen abstraction by up to 30 kJ/mol. A correlation (R(2) = 0.72) between the transition-state energies and the corresponding substrate radical energies has been established. Using this correlation is significantly less time-demanding than using the porphyrin model to determine the activation energies. We have used this correlation on monosubstituted phenols to rationalize the effect of the various substituents in the drug compounds. In addition to facilitating a chemical interpretation, the approach is sufficiently fast and reliable to be used as an in silico method in the design of new compounds with improved metabolic stability.

AB - Many drug compounds are oxidized by cytochrome P450 (CYP) enzymes to form reactive metabolites. This study presents density functional theory calculations of the CYP-mediated metabolism of acetaminophen and a series of related compounds that can form reactive metabolites by hydrogen abstraction. The substitution pattern affects the activation barrier for hydrogen abstraction by up to 30 kJ/mol. A correlation (R(2) = 0.72) between the transition-state energies and the corresponding substrate radical energies has been established. Using this correlation is significantly less time-demanding than using the porphyrin model to determine the activation energies. We have used this correlation on monosubstituted phenols to rationalize the effect of the various substituents in the drug compounds. In addition to facilitating a chemical interpretation, the approach is sufficiently fast and reliable to be used as an in silico method in the design of new compounds with improved metabolic stability.

U2 - 10.1021/ci500653b

DO - 10.1021/ci500653b

M3 - Journal article

C2 - 25658971

VL - 55

SP - 660

EP - 666

JO - Journal of Chemical Information and Modeling

JF - Journal of Chemical Information and Modeling

SN - 1549-9596

IS - 3

ER -

ID: 140712647