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Prediction of activation energies for hydrogen abstraction by cytochrome P450

Olsen, Lars ; Rydberg, Patrik LU ; Rod, Thomas H. and Ryde, Ulf LU orcid (2006) In Journal of Medicinal Chemistry 49(22). p.6489-6499
Abstract
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,... (More)
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. (Less)
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publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Medicinal Chemistry
volume
49
issue
22
pages
6489 - 6499
publisher
The American Chemical Society (ACS)
external identifiers
  • wos:000241553700007
  • scopus:33750486521
ISSN
1520-4804
DOI
10.1021/jm060551l
language
English
LU publication?
yes
additional info
The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Theoretical Chemistry (S) (011001039)
id
8cdd6f8c-09b8-4ecc-baf4-39364f392a1c (old id 378791)
date added to LUP
2016-04-01 12:09:57
date last changed
2021-02-17 06:57:39
@article{8cdd6f8c-09b8-4ecc-baf4-39364f392a1c,
  abstract     = {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.},
  author       = {Olsen, Lars and Rydberg, Patrik and Rod, Thomas H. and Ryde, Ulf},
  issn         = {1520-4804},
  language     = {eng},
  number       = {22},
  pages        = {6489--6499},
  publisher    = {The American Chemical Society (ACS)},
  series       = {Journal of Medicinal Chemistry},
  title        = {Prediction of activation energies for hydrogen abstraction by cytochrome P450},
  url          = {http://dx.doi.org/10.1021/jm060551l},
  doi          = {10.1021/jm060551l},
  volume       = {49},
  year         = {2006},
}