Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

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)
Please use this url to cite or link to this publication:
author
; ; and
organization
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
2023-03-26 22:05:03
@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          = {{https://lup.lub.lu.se/search/files/135493803/89_ts_pred.pdf}},
  doi          = {{10.1021/jm060551l}},
  volume       = {{49}},
  year         = {{2006}},
}