Structure-Based Site of Metabolism (SOM) prediction of ligand for CYP3A4 Enzyme: Comparison of Glide XP and Induced Fit Docking (IFD)

Metabolism is one of the prime reasons where most of the drugs fail to accomplish their clinical trials. The enzyme CYP3A4, which belongs to the superfamily of cytochrome P450 enzymes (CYP) helps in the metabolism of a large number of drugs in the body. The enzyme CYP3A4 catalyzes mainly the oxidative chemical processes and also shows a very broad range of ligand specificity. Understanding of compound’s structure where oxidation would take place is crucial for the successful modification of molecules in order to avoid unwanted metabolism and to increase its bioavailability. For this reason, it is required to know the site of metabolism (SOM) of the compounds, where compounds undergo enzymatic oxidation. It can be identified by predicting the accessibility of the substrate’s atom toward oxygenated Fe atom of heme in a CYP protein. The CYP3A4 enzyme is a highly flexible enzyme and can take significantly different conformations depending on the ligand with which it is being bound. Here in, we studied the ability of the Glide XP and Induced Fit docking (IFD) tool of Schrodinger software suite to reproduce the binding mode of co-crystalized ligands into six X-ray crystallographic structures. We extend our studies for the prediction of SOM for compounds whose experimental SOM is reported but ligand-enzyme complex crystal structure is not available in Protein Data Bank (PDB). It was observed that IFD reproduces the exact binding mode of available co-crystallized structures and correctly predicted the SOM of experimentally reported compounds.