Improvement of Site of Metabolism Predictions for CYP3A4 by Using Discriminant Analysis of Compound Preference of CYP3A4 X‐Ray Structural Conformers and Subsequent Docking

Metabolism plays a significant role in failure of drugs to carry out their intended action in the body. Drugs and other xenobiotics in the body are mainly biotransformed through oxidation reactions catalyzed by cytochrome P450 enzymes, in particular the CYP3A4 isoform. This enzyme is well known for its very wide substrate specificity and promiscuity. Understanding where in a compound's structure the enzymatic oxidation would take place, i.e. site of metabolism (SOM), is crucial for successful modification of molecules in order to avoid unwanted metabolism. Several in silico methods have been developed for SOM predictions including docking based methods. One of the benefits of docking based methods is that they provide insight into the structure of the drug-enzyme complex. However, crystallographic studies of CYP3A4 have showed that the structure of this enzyme may obtain substantially different conformations depending on the structure of the ligand it is cocrystallized with. Therefore, it is not straight forward to decide which of the different crystal structures of CYP3A4 should be used for SOM prediction when using docking methods. Here we show that simple discriminative models allow selection of CYP3A4 structural conformer to yield better SOM predictions for each individual substrate.