Reduced vdW Radius Improves Site of Metabolism Predictions Using X‐Ray Structure of CYP2D6

The major oxidative metabolic degradation of drugs occurs through cytochrome P450 enzymes, which has very wide substrate specificity. Therefore it is crucial to be able to determine the exact position for enzymatic oxidation. Several methods have been developed for site of metabolism (SOM) prediction in silico, including docking based methods. One of the benefits of docking based methods is that it visualizes the drug-enzyme complex and facilitate antidesign towards specific interactions. Recently, the crystal structure of one of the cytochrome P450 enzyme isoforms, CYP2D6, has been published. Here we investigate the feasibility to utilize this structure for SOM predictions using docking. It was found that the intact structure was not well suited for SOM predictions. Reduction of vdW radius of enzyme atoms in the docking grid significantly improved predictions, indicating that the atoms of some of the sidechains of the solved CYP2D6 crystal structure conformation interfere with docked ligands atoms, thus, preventing accurate dockings and SOM predictions.