Cytochrome P450 proteins are membrane-associated heme proteins that metabolize physiologically important compounds. While P450s are important for normal dietary metabolism, they also play a role in processing xenobiotics. Examples include environmental contaminants and drugs. Several enantiomeric molecules (warfarin, flurbiprofen, phenprocoumon, and fluoxetine) were modeled using Sybyl-X from Tripos, Inc. to ascertain the effect of chirality on the oxidative metabolism by CYP2C9. The goal was to determine which form of the molecules (S/R) was preferred for docking in the CYP2C9 protein. In most cases, the difference between the S and R form is significant. According to previous research, S-warfarin is metabolized by CYP2C9 nearly 1000-fold better than R-warfarin, but the molecular interactions responsible for this difference are unknown. Once the specificity of the molecules was confirmed, the intermolecular interactions were identified. The data obtained from identifying these interactions allows for mutation of specific residues and confirms their importance in drug metabolism.

Investigation of chirality and its effects on the computational docking of various enantiospecific molecules with CYP2C9

243rd National Meeting (2012)

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