Because chiral drugs make up 50% of drugs on the market, examination of their metabolism could advance understanding of why they are effective.  Frequently chiral drugs are cleared much more favorably in one conformation than in the other.  Due to their nature and position in the channel where oxidation occurs, certain residues, or amino acids, could act to steer metabolism based on the drug's stereochemistry.  Computational approaches including molecular dynamics were performed to simulate metabolism. A novel approach involved the use of the Lennard-Jones potential to estimate the stabilizing energy afforded by each residue to the enzyme-ligand complex.  The residues with the largest difference in energy between configurations of drugs were identified for multiple drugs.  Several residues, including PHE476, showed much more favorable interaction with one enantiomer of a drug than with the other enantiomer.  Such differences based on chirality lent themselves well to the idea of residues steering metabolism.

Application of computational docking to examine metabolism of chiral drugs by CYP2C9

245th National Meeting (2013)

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