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The molecular basis for the inhibition of human cytochrome P450 1A2 by oroxylin and wogonin

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Abstract

In our previous kinetics studies the natural products oroxylin and wogonin were shown to have strong biological affinity for, and inhibitory effects against, human cytochrome P450 1A2, with IC50 values of 579 and 248 nM, respectively; this might lead to the occurrence of drug–drug interactions when co-administered clinically. However, their inhibitory mechanisms against 1A2 remain elusive. In this study, molecular docking and molecular dynamics simulations were performed to better understand the molecular basis of their inhibitory mechanisms towards 1A2. Structural analysis revealed that oroxylin has a different binding pattern from wogonin and another very strongly binding inhibitor α-naphthoflavone (ANF, IC50 = 49 nM). The O7 atom of oroxylin forms hydrogen bonds with the OD1/OD2 atoms of Asp313, which is not observed in the 1A2–wogonin complex. Because of energetically unfavorable repulsions with the methoxy group at the 6 position of the oroxylin ring, significant conformational changes were observed for the sidechain of Thr118 in the MD simulated model. As a result, the larger and much more open binding-site architecture of the 1A2–oroxylin complex may account for its weaker inhibitory effect relative to the 1A2–ANF complex. Energy analysis indicated that oroxylin has a less negative predicted binding free energy of −19.8 kcal/mol than wogonin (−21.1 kcal/mol), which is consistent with our experimental assays. Additionally, our energy results suggest that van der Waals/hydrophobic and hydrogen-bonding interactions are important in the inhibitory mechanisms of oroxylin whereas the former is the underlying force responsible for strong inhibition by ANF and wogonin.

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Acknowledgments

We are grateful for financial support from the Natural Science Foundation of China (21103234), the Natural Science Foundation of Guangdong Province (S2011030003190), the Science Foundation of the Department of Education in Guangdong Province (CXZD1006), the Science Foundation of Guangzhou City (2010Y1-C531), and Fundamental Research Funds for the Central Universities (10ykjc20).

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Authors and Affiliations

  1. School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China

    Yong-Xian Shao, Peng Zhao, Zhe Li, Ming Liu, Peiqing Liu, Min Huang & Hai-Bin Luo

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  1. Yong-Xian Shao
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  2. Peng Zhao
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  3. Zhe Li
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  4. Ming Liu
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  5. Peiqing Liu
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  6. Min Huang
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  7. Hai-Bin Luo
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Correspondence to Hai-Bin Luo.

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Yong-Xian Shao and Peng Zhao contributed equally.

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Shao, YX., Zhao, P., Li, Z. et al. The molecular basis for the inhibition of human cytochrome P450 1A2 by oroxylin and wogonin. Eur Biophys J 41, 297–306 (2012). https://doi.org/10.1007/s00249-011-0785-1

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  • DOI: https://doi.org/10.1007/s00249-011-0785-1

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