Cytochrome P450 (CYP) enzymes play a critical role in detoxication and bioactivation of xenobiotics; thus, the prediction of biotransformation rates and regioselectivity of CYP enzymes toward substrates is an important goal in toxicology and pharmacology.  We have applied the semi-empirical quantum chemistry method SAM1 to rapidly estimate relative activation enthalpies (?H�) for the hydroxylation of aliphatic carbon centers of various substrates. The ?H� were determined via a reaction path calculation, in the reverse direction (RRP), using the iron-hydroxo-porphine intermediate and the substrate radical. The SAM1 ?H�, calculated via unrestricted Hartree-Fock (UHF) and configuration interaction (CI) formalisms, were compared with density functional theory (DFT) B3LYP activation energies and showed R2 ranging from 0.69 to 0.89.  SAM1 RRP calculation times were, on average, over 200 times faster than those for the corresponding forward reaction path DFT calculations, suggesting that this approach can rapidly estimate DFT activation energy and substrate hydroxylation rates.

Rapid estimation of activation enthalpies for cytochrome-P450-mediated hydroxylations

242nd National Meeting (2011)

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