The unmarked potential drug molecule azamulin has been found to be a specific inhibitor of CYP3A4 and CYP3A5 in recent years, but this molecule also shows different binding ability and affinity to the two CYP3A isoforms. In order to explore the microscopic mechanism, conventional molecular dynamics (MD) simulation methods were performed to study the dynamic interactions between two isoforms and azamulin. The simulation results show that the binding of the ligand leads to different structural properties of two CYP3A proteins. First of all, compared with apo-CYP3A4, the binding of the ligand azamulin can lead to changes in the structural flexibility of CYP3A4, i.e., holo-CYP3A4 is more flexible than apo-CYP3A4. The structural changes of CYP3A5 are just the opposite. The ligand binding increases the rigidity of CYP3A5. Furthermore, the representative structures of the production phase in the MD simulation were in details analyzed to obtain the microscopic interactions between the ligand azamulin and two CYP3A isoforms at the atomic level. It is speculated that the difference of composition and interaction of the active sites is the fundamental cause of the change of structural properties of the two proteins.Communicated by Ramaswamy H. Sarma.
Keywords: Cytochrome; affinity; azamulin; binding free energy; molecular dynamics simulation; protein–ligand interaction.