Isoform-selective inhibition of chrysin towards human cytochrome P450 1A2. Kinetics analysis, molecular docking, and molecular dynamics simulations.

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He L, He F, Bi H, Li J, Zeng S, Luo HB, Huang M

Isoform-selective inhibition of chrysin towards human cytochrome P450 1A2. Kinetics analysis, molecular docking, and molecular dynamics simulations.

Bioorg Med Chem Lett. 2010 Oct 15;20(20):6008-12. doi: 10.1016/j.bmcl.2010.08.072. Epub 2010 Aug 20.

PubMed ID

20832301 [ View in PubMed

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Abstract

Our kinetics studies demonstrated that the nature product chrysin exhibited a high inhibitory affinity of 54 nM towards human cytochrome P450 1A2 and was comparable to alpha-naphthoflavone (49 nM), whereas it represented a moderate affinity of 5225 nM against human cytochrome P450 2C9. However, it remains unclear how this inhibitor selectively binds 1A2. To better understand the isoform selectivity of chrysin, molecular docking and molecular dynamics simulations were performed. Chrysin formed a strong H-bond with Asp313 of 1A2. The stacking interactions with Phe226 also contributed to its tight binding to 1A2. The larger and much more open active site architectures of 2C9 may explain the weaker inhibitory affinity of chrysin towards 2C9. The predicted binding free energies suggest that chrysin preferred 1A2 (DeltaG(bind, pred)=-23.11 kcal/mol) to 2C9 (-20.41 kcal/mol). Additionally, the present work revealed that 7-hydroxy-flavone bound to 1A2 in a similar pattern as chrysin and represented a slightly less negative predicted binding free energy, which was further validated by our kinetics analysis (IC(50)=240 nM). Results of the study can provide insight for designing novel isoform-selective 1A2 inhibitors.

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Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
alpha-Naphthoflavone	Cytochrome P450 1A2	IC 50 (nM)	49	N/A	N/A	Details