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Assessment of CYP3A4 Inhibition by Selected Flavonoids - a Molecular Docking Approach

Introduction: Flavonoids are class of compounds found in fruits and vegetables. Cytochrome P450 3A4 is one of the major enzymes for metabolism of xenobiotics and as such susceptible to flavonoid-drug interactions. In our previous study we have shown that acacetin, apigenin, and chrysin act as reversible inhibitors while chrysin dimethylether, isorhamnetin, pinocembrin, and tangeretin act as irreversible inhibitors. The objective of this work was to assess potential binding sites of these flavonodis to CYP3A4. Materials and Methods: Molecular docking of aforementioned inhibitors and non-inhibiting flavonoids (3, 6-dihydroxyflavon, tamarixetin) to cytochrome CYP3A4 was performed using AutoDock 4.2.6. with AutoDockTools 1.5.6. Results: Results of this research show that different flavonoids bind to different sites of the CYP3A4 enzyme. While 3, 6-dihydroxyflavon binds outside of the active site, acacetin and apigenin are located perpendicularly to the hem group, with their hydroxy group on the B ring directed to hem. Chrysin, chrysin dimethylether and pinocembrin are also located in the cavity, but parallelly to the hem group. Isorhamnetin, tamarixetin and tangeretin are located at the entrance of the cavity. Conclusion: Molecular docking can, to some extent explain observed patterns of CYP3A4 inhibition observed with analyzed flavonoids. Flavonoids binding outside of the active site have no impact on the activity of the enzyme or they can influence its activity through allosteric modifications. Flavonoids located perpendicularly or parallelly to the hem group can directly influence enzyme activity, while flavonoids located at the entrance can manifest their activity by blocking the access to the enzyme.

CYP3A4; flavonoids; inhibition; molecular modeling

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