Our previous kinetics studies demonstrate that the natural product galangin exhibits a high-affinity inhibition of 153 nM towards human cytochrome P450 1A2. However, much less is known about the inhibitory mechanism of galangin against 1A2. To better understand the inhibitory mechanism of galangin towards 1A2, a modeling study including molecular docking and molecular dynamics simulations was performed. The binding pattern after molecular dynamics simulations reveals that galangin represents a similar binding pattern as another strong inhibitor α-naphthoflavone with a few exceptions. The O7 atom of galangin forms an H-bond with the O atom of Asn312. An intramolecular H-bond is observed between the O5 and O4 atoms of galangin. Energetic analysis indicates that galangin exhibits a less negative predicted binding free energy of -22.61 kcal/mol than α-naphthoflavone (-23.54 kcal/mol), which is consistent with inhibitory experiment (153 nM and 49 nM). Additionally, our results suggest that the inhibitory mechanism of galangin is mainly dominated by electrostatic/H-bond and hydrophobic/van der Waals interactions. The present work also revealed that the additional 4' hydroxyl group at the B ring would weaken the intermolecular interactions between kaempferol and 1A2, which was validated by our kinetics experiment (IC50 = 1 490 nM).
Keywords: Galangin, CYP 1A2, Inhibition, MD stimulations, Binding free energy
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