Prediction of activation energies for hydrogen abstraction by cytochrome P450
Olsen, Lars ; Rydberg, Patrik LU ; Rod, Thomas H. and Ryde, Ulf LU
(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:
https://lup.lub.lu.se/record/378791
- author
- Olsen, Lars
; Rydberg, Patrik
LU
; Rod, Thomas H.
and Ryde, Ulf
LU
- organization
- publishing date
- 2006
- 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}},
}