| Abstract
| - We have estimated the activation energy for hydrogen abstraction by compound I in cytochrome P450 fora diverse set of 24 small organic substrates using state-of-the-art density functional theory (B3LYP). Wethen 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 (meanabsolute error of 3−4 kJ/mol) or by calculating the bond dissociation energy, without relaxation of theradical (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 sp2 or aromatic groups, ethers/thioethers, and amines,respectively, which gives a very simple and predictive model. Finally, some of the less demanding methodsare applied to study the CYP3A4 metabolism of progesterone and dextromethorphan.
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