Xenobiotic compounds such as pharmaceutical drugs are metabolized by cytochrome P450, which contains the enantiospecific subfamily CYP2C9.  Due to CYP2C9’s involvement in metabolizing drugs in the liver, research of the interactions between this enzyme and drugs could lead to drugs that are engineered with less severe side effects and greater productivity. Our previous research studies have demonstrated the enantiospecificity of certain residues on CYP2C9 such as Leu366, Phe100, and Phe476.  The molecular modeling software, Sybyl-X, was used to mutate these hotspots to increase or decrease the polarity.  After mutating the residues, molecular dynamics simulations were performed with aggregates and constraints that positioned and navigated the ligand towards the heme active site of CYP2C9.  The ligands under examination were common NSAIDs such as naproxen, zaltoprofen, and ketoprofen that all contain one chiral center producing two enantiomers for each drug.  Data collected from the molecular dynamics runs, based on van der Waals and hydrogen bonding interacts between the ligand and surrounding residues, were compared to the unmutated residues using the Lennard-Jones potential energy equation.  Some of the mutations caused an increase in enantiospecificity of the previously favored enantiomer, while others caused a complete shift in enantiospecificity. <br/> <br/><br/><br/>

Computational simulations of chiral drug metabolism by mutated CYP2C9

253rd National Meeting (2017)

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