title: Prediction of activation energies for hydrogen abstraction by cytochrome p450.
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.
authors.affiliation: Department of Medicinal Chemistry, The Danish University of Pharmaceutical Sciences, 2 Universitetsparken, DK-2100 Copenhagen, Denmark. lo@dfuni.dk
authors.forename: Lars
authors.initials: L
authors.lastname: Olsen
authors.forename: Patrik
authors.initials: P
authors.lastname: Rydberg
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Rod
authors.forename: Ulf
authors.initials: U
authors.lastname: Ryde
mesh_terms: D000465:Algorithms; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D019295:Computational Biology; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000378:metabolism*; D006859:Hydrogen / Q000737:chemistry*; D007501:Iron / Q000737:chemistry; D008956:Models, Chemical; D004364:Pharmaceutical Preparations / Q000737:chemistry
chemical_list: D004364:Pharmaceutical Preparations; D006859:Hydrogen; D003577:Cytochrome P-450 Enzyme System; D007501:Iron