A Comprehensive Analysis of Human CYP3A4 Crystal Structures as a Potential Tool for Molecular Docking-Based Site of Metabolism and Enzyme Inhibition Studies

The notable ability of human liver cytochrome P450 3A4 (CYP3A4) to metabolize diverse xenobiotics encourages researchers to explore in-depth the mechanism of enzyme action. Numerous CYP3A4 protein crystal structures have been deposited in protein data bank (PDB) and are majorly used in molecular docking analysis. The quality of the molecular docking results depends on the three-dimensional CYP3A4 protein crystal structures from the PDB. Present review endeavors to provide a brief outline of some technical parameters of CYP3A4 PDB entries as valuable information for molecular docking research. PDB entries between 22 April 2004 and 2 June 2021 were compiled and the active sites were thoroughly observed. The present review identified 76 deposited PDB entries and described basic information that includes CYP3A4 from human genetic, Escherichia coli (E. coli) use for protein expression, crystal structure obtained from X-ray diffraction method, taxonomy ID 9606, Uniprot ID P08684, ligand–protein structure description, co-crystal ligand, protein site deposit and resolution ranges between 1.7[Formula: see text]Å and 2.95[Formula: see text]Å. The observation of protein–ligand interactions showed the various residues on the active site depending on the ligand. The residues Ala305, Ser119, Ala370, Phe304, Phe108, Phe213 and Phe215 have been found to frequently interact with ligands from CYP3A4 PDB. Literature surveys of 17 co-crystal ligands reveal multiple mechanisms that include competitive inhibition, noncompetitive inhibition, mixed-mode inhibition, mechanism-based inhibition, substrate with metabolite, inducer, or combination modes of action. This overview may help researchers choose a trustworthy CYP3A4 protein structure from the PDB database to apply the protein in molecular docking analysis for drug discovery.