Chemistry Department, Vassar College, Poughkeepsie, NY 12604, USA.
Computing and Information Services, Vassar College, Poughkeepsie, NY 12604, USA.
Molecules. 2020 Jul 10;25(14):3158. doi: 10.3390/molecules25143158.
Coumarins are plant-derived secondary metabolites. The crystal structure of three coumarins-bergamottin, osthole and fraxidin-are described and we analyze intermolecular interactions and their role in crystal formation. Bergamottin is a furanocoumarin found in citrus plants, which is a strong inhibitor of the principal human metabolizing enzyme, cytochrome P450 3A4 (CYP3A4). The crystal structure determinations of three coumarins give us the geometrical parameters and reveal the parallel-displaced π-π stacking and hydrogen bonding intermolecular interactions used for molecular assembly in the crystal structure. A quite strong (less than 3.4 Å) stacking interaction of bergamottin appears to be a determining feature that distinguishes it from other coumarins studied in this work. Our DFT computational studies on the three natural products of the same coumarin family docked into the active site of CYP3A4 (PDB 4D78) show different behavior for these coumarins at the active site. When the substrate is bergamottin, the importance of π-π stacking and hydrogen bonding, which can anchor the substrate in place, appears fundamental. In contrast, fraxidin and osthole show carbonyl coordination to iron. Our docking calculations show that the bergamottin tendency towards π-π stacking is important and likely influences its interactions with the heme group of CYP3A4.
香豆素是植物次生代谢产物。本文描述了三种香豆素-佛手柑内酯、蛇床子素和瑞香素的晶体结构，并分析了它们的分子间相互作用及其在晶体形成中的作用。佛手柑内酯是一种存在于柑橘类植物中的呋喃香豆素，是人类主要代谢酶细胞色素 P450 3A4（CYP3A4）的强抑制剂。三种香豆素的晶体结构测定为我们提供了几何参数，并揭示了在晶体结构中用于分子组装的平行位移 π-π 堆积和氢键分子间相互作用。佛手柑内酯相当强的（小于 3.4 Å）堆积相互作用似乎是将其与本工作中研究的其他香豆素区分开来的决定性特征。我们对同一香豆素家族的三种天然产物在 CYP3A4 活性部位（PDB 4D78）中的 DFT 计算研究表明，这些香豆素在活性部位的行为不同。当底物是佛手柑内酯时，π-π 堆积和氢键的重要性（可以将底物固定在适当的位置）似乎是基础的。相比之下，瑞香素和蛇床子素显示出与铁的羰基配位。我们的对接计算表明，佛手柑内酯的π-π 堆积倾向很重要，可能会影响其与 CYP3A4 血红素基团的相互作用。
