Approximately 50% of pharmaceutical drugs currently available on the market are chiral. Cytochrome P450 is a well-known superfamily of enzymes involved in the oxidative metabolism of vast ranges of pharmaceutical drugs. Specifically, the liver enzyme CYP2C9 has been known to be the main metabolite contributor for at least forty drugs and to metabolize one enantiomer better than the other. Warfarin is a classic example of an enantiospecific drug where the S-enantiomer metabolizes 1000 times better than the R-enantiomer. Crystallized protein structures provide the medium to run molecular dynamics and analyze intermolecular forces. Using molecular dynamics through a molecular modeling suite Sybyl-X, computational approaches were performed to simulate the oxidation reaction and to determine which interacting amino acid residues had stabilizing effects on the enzyme-ligand complex. Jointly, thermodynamics and kinetics work to guide the favorability of interactions between drugs and enzymes. Residues present in CYP2C9 such as ARG108, ILE205, LEU208, PHE476, and THR301, in particular, interact strongly with the drug enantiomers by means of Van der Waals forces, hydrogen bonding, and π-stacking. Significant residue energy differences between R and S enantiomers were identified for multiple chiral drugs used in the treatment of acid reflux, type 2 diabetes, and cancer.

Using molecular dynamics to computationally simulate metabolic enantiospecificity of CYP2C9

249th National Meeting (2015)

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