Prediction of activation energies for hydrogen abstraction by cytochrome p450
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Prediction of activation energies for hydrogen abstraction by cytochrome p450. / Olsen, Lars; Rydberg, Patrik; Rod, Thomas Holm; Ryde, Ulf.
In: Journal of Medicinal Chemistry, Vol. 49, No. 22, 2006, p. 6489-6499.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Prediction of activation energies for hydrogen abstraction by cytochrome p450
AU - Olsen, Lars
AU - Rydberg, Patrik
AU - Rod, Thomas Holm
AU - Ryde, Ulf
PY - 2006
Y1 - 2006
N2 - We have estimated the activation energy for hydrogen abstraction by compound I in cytochrome P450 for a diverse set of 24 small organic substrates using state-of-the-art density functional theory (B3LYP). We then show that these results can be reproduced by computationally less demanding methods, for example, by using small organic mimics of compound I with both B3LYP and the semiempirical AM1 method (mean absolute error of 3-4 kJ/mol) or by calculating the bond dissociation energy, without relaxation of the radical (B3LYP) or estimated from three-point fit to a Morse potential (AM1; errors of 4 and 5 kJ/mol, respectively). We can assign activation energies of 74, 61, 53, 47, and 30 kJ/mol to primary carbons, secondary/tertiary carbons, carbons with adjacent sp(2) or aromatic groups, ethers/thioethers, and amines, respectively, which gives a very simple and predictive model. Finally, some of the less demanding methods are applied to study the CYP3A4 metabolism of progesterone and dextromethorphan.
AB - We have estimated the activation energy for hydrogen abstraction by compound I in cytochrome P450 for a diverse set of 24 small organic substrates using state-of-the-art density functional theory (B3LYP). We then show that these results can be reproduced by computationally less demanding methods, for example, by using small organic mimics of compound I with both B3LYP and the semiempirical AM1 method (mean absolute error of 3-4 kJ/mol) or by calculating the bond dissociation energy, without relaxation of the radical (B3LYP) or estimated from three-point fit to a Morse potential (AM1; errors of 4 and 5 kJ/mol, respectively). We can assign activation energies of 74, 61, 53, 47, and 30 kJ/mol to primary carbons, secondary/tertiary carbons, carbons with adjacent sp(2) or aromatic groups, ethers/thioethers, and amines, respectively, which gives a very simple and predictive model. Finally, some of the less demanding methods are applied to study the CYP3A4 metabolism of progesterone and dextromethorphan.
KW - Former Faculty of Pharmaceutical Sciences
U2 - 10.1021/jm060551l
DO - 10.1021/jm060551l
M3 - Journal article
C2 - 17064067
VL - 49
SP - 6489
EP - 6499
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 22
ER -
ID: 38165618