CYP450 is the largest super-family of proteins known in biology; they are known to metabolize steroids (endobiotic substrates) and drugs (xenobiotic substrates). The particular P450 enzyme of interest is CYP2C9, a phase I drug-metabolizing cytochrome P450 enzyme isoform that plays a major role in the oxidation of both xenobiotic and endogenous compounds. This enzyme was investigated to determine interactions with a variety of chiral drugs including warfarin and flurbiprofen. CYP2C9 is known to metabolize S-warfarin over one thousand times more efficiently than R-warfarin, but the molecular interactions responsible for this difference are unknown. Using Sybyl-X software from Tripos, Inc., docking solutions for the 1OG5 crystal structure (www.rcsb.org) were generated using molecular dynamics simulations. The intermolecular forces between the different enantiomers and the enzyme affect the overall docking affinity. These observed interactions will contribute to further projects aimed at understanding the effect chirality of the substrate plays in overall metabolic activity.

Using computational docking to assess the role of chirality on drug metabolism by CYP2C9

243rd National Meeting (2012)

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