CYP2C9, a protein found in the liver, is known to be the enzyme that oxidizes up to 20% of all drugs undergoing phase-I metabolism. The method in which this enzyme metabolizes xenobiotics such as flurbiprofen, ibuprofen, and suprofen, and the factors that affect its efficiency are widely unknown. However, it is apparent that this enzyme exhibits high enantiospecificity that can affect the rate at which certain enantiomers of a specific drug are oxidized. By using Sybyl-X’s computational docking program, data was collected to determine interactions for each enantiomer of specific drugs favorable for metabolism. The R and S enantiomers of the single chiral center NSAIDS (flurbiprofen, ibuprofen, and suprofen) were navigated through CYP2C9’s protein channel to the heme active site region. The resulting intermolecular interactions between each ligand and the enzyme were recorded and analyzed. The targeted protein was then mutated at predetermined “hotspots” with amino acid changes that were based on polarity. Leucine 366, which is a nonpolar amino acid, was swapped for asparagine, an amino acid with similar structure but increased polarity. Two other hotspots that were targeted were phenylalanine 100 and phenylalanine 476. Both residues were mutated with tyrosine. Resulting data was collected and analyzed to determine which enantiomer of each ligand was preferred for binding under each set of conditions.

CYP2C9 and the mutations that affect NSAID oxidation efficiency

253rd National Meeting (2017)

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