School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China.
Bioorg Med Chem Lett. 2010 Oct 15;20(20):6008-12. doi: 10.1016/j.bmcl.2010.08.072. Epub 2010 Aug 20.
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 α-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 (ΔG(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.
我们的动力学研究表明，天然产物白杨素对人细胞色素 P450 1A2 具有高抑制亲和力，其半数最大抑制浓度（IC50）为 54 nM，与α-萘黄酮（49 nM）相当，而对人细胞色素 P450 2C9 的亲和力则适中，IC50 为 5225 nM。然而，目前尚不清楚这种抑制剂如何选择性地结合 1A2。为了更好地理解白杨素的同工酶选择性，我们进行了分子对接和分子动力学模拟。白杨素与人细胞色素 P450 1A2 的 Asp313 形成了强氢键。与 Phe226 的堆积相互作用也有助于其与 1A2 的紧密结合。2C9 具有更大、更开放的活性位点结构，可能解释了白杨素对 2C9 的抑制亲和力较弱的原因。预测的结合自由能表明，白杨素优先与 1A2 结合（ΔG(bind, pred)=-23.11 kcal/mol），而不是与 2C9 结合（-20.41 kcal/mol）。此外，本研究还表明，7-羟基黄酮与人细胞色素 P450 1A2 的结合模式与白杨素相似，并且预测的结合自由能略低，这一结果通过我们的动力学分析（IC50=240 nM）得到了进一步验证。研究结果可为设计新型同工酶选择性 1A2 抑制剂提供思路。
