Density functional theory study on the formation of reactive benzoquinone imines by hydrogen abstraction
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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 journal › Journal article › Research › peer-review
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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