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目的:我们先前的体外肝微粒体抑制活性实验,已证实芹菜素和山萘酚对细胞色素CYP 1A2有较强的抑制作用。然而,其抑制机理仍然未知。分子模拟方法能更好了解这2个天然产物对1A2的抑制机理。方法:采用分子对接、分子动力学模拟及结合自由能计算的方法,研究它们对1A2的抑制作用。结果:芹菜素和山萘酚对1A2的预测结合自由能分别是-18.01和-16.40 kcal/mol,这与实验抑制活性结果一致。在1A2结合口袋中,残基呈平面性排列,与平面芹菜素和山萘酚存在紧密的范德华和疏水相互作用,因而小分子有较强的抑制作用。此外,活性位点残基也与小分子发生氢键和盐桥等相互作用,使小分子在结合口袋中的位置得到固定。
OBJECTIVE: Our previous in vitro liver microsomal inhibitory activity assay demonstrated that apigenin and kaempferol have a potent inhibitory effect on cytochrome CYP 1A2. However, the mechanism of its suppression is still unknown. The molecular simulation method can better understand the inhibition mechanism of 1A2 by these two natural products. Methods: The molecular docking, molecular dynamics simulation and binding free energy calculation method to study their inhibition of 1A2. RESULTS: The predicted free energy binding of apigenin and kaempferol to 1A2 was -18.01 and -16.40 kcal / mol, respectively, consistent with the experimental inhibitory activity. In the 1A2 binding pocket, the residues were arranged planarly, interacting closely with van der Waals and hydrophobic interactions of planar apigenin and kaempferol, and thus have small inhibitory effects. In addition, active site residues and small molecules hydrogen bond and salt bridge interaction, so that small molecules in the binding pocket position is fixed.