In previous research, the enantiospecificity of CYP2C9, the most enantiospecific member of a family of enzymes known as cytochrome P450’s, was examined. CYP2C9 is known for its involvement in oxidation reactions in the liver that aid the metabolism of xenobiotic molecules, namely pharmaceuticals. An analysis of the interactions between the residues of CYP2C9 and drugs could lead to the reduction of side effects and overall improvement in drug manufacturing. In the aforementioned previous research, certain residues were found to have significant effects on enantiospecificity: Leu366, Phe100, and Phe476. Each of these residues was systematically mutated using molecular modeling software, Sybyl-X, and molecular dynamics simulations using constraints to emulate an attractive force between ligand and the mutated CYP2C9 were conducted. Three chiral ligands were studied, all of which are NSAIDS: ketoprofen, naproxen, and zaltoprofen. Upon completion of the molecular dynamics simulations, energies by residue were calculated based on the Van der Waals and hydrogen bonding interactions between individual atoms of the ligand and residues within a four angstrom radius of the ligand, using the same method as performed previously. These energy calculations were compared to the non-mutated CYP2C9 dynamics analyses to view differences in results. Subtracting the energies of each enantiomer from its counterpart reveals the enantiospecificity of each residue. In some cases, the mutation of CYP2C9’s residues increased the preference of an already preferred enantiomer, while other mutations shifted the preference to the other enantiomer entirely. This project was supported by the Arkansas INBRE program, with grants from the National Center for Research Resources - NCRR (P20RR016460) and the National Institute of General Medical Sciences - NIGMS (P20 GM103429) from the National Institutes of Health.<br/>

Computational investigations of enantiospecificity of mutated CYP2C9

251st National Meeting (2016)

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