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

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

SN - 1549-9596

VL - 55

SP - 660

EP - 666

JO - Journal of Chemical Information and Modeling

JF - Journal of Chemical Information and Modeling

IS - 3

ER -