Interaction study of engeletin toward cytochrome P450 3A4 and 2D6 by multi-spectroscopy and molecular docking

The inhibitory effects of engeletin on the activities of human cytochrome P450 3A4 and 2D6 (CYP3A4 and CYP2D6) were investigated by enzyme kinetics, multi-spectroscopy and molecular docking. Engeletin was found to strongly inhibit CYP3A4 and CYP2D6, with the IC₅₀ of 1.32 μM and 2.87 μM, respectively. The inhibition modes of engeletin against CYP3A4 and CYP2D6 were a competitive type and a mixed type, respectively. The fluorescence of the two CYPs was quenched statically by engeletin, which was bound to CYP3A4 stronger than to CYP2D6 at the same temperature. Circular dichroism spectroscopy, three-dimensional fluorescence, ultraviolet-visible spectroscopy and synchronous fluorescence confirmed that the conformation and micro-environment of the two CYPs protein were changed after binding with engeletin. Molecular docking, ultraviolet-visible spectroscopy and the fluorescence data revealed that engeletin had strong binding affinity to the two CYPs through hydrogen and van der Waals forces. The findings here suggested that engeletin may cause the herb-drug interactions for its inhibition of CYP3A4 and CYP2D6 activities.