七-(2,6-二甲基)-β-环糊精对木犀草素的增溶研究

Study of Solubility Enhancement of Luteolin by Heptakis-(2, 6-dimethyl)-β-cyclodextrin

关键词:  相溶解度  七-(2,6-二甲基)-β-环糊精  木犀草素  分子对接  分子动力学

Key words:  phase solubility  heptakis-(2,6-dimethyl)-β-cyclodextrin  luteolin  molecular docking  molecular dynamics

摘要:

目的 研究5种环糊精对木犀草素（luteolin，Lut）的增溶作用，探讨了环糊精对难溶性药物的增溶机理。方法 采用相溶解度法比较了β-环糊精（β-cyclodextrin，β-CD）、γ-环糊精、2-羟丙基-β-环糊精、七-（2，6-二甲基）-β-环糊精[heptakis-（2，6-dimethyl）-β-cyclodextrin，DM-β-CD]与6-葡萄糖基-β-环糊精对Lut的增溶作用，采用傅里叶变换红外光谱法（Fourier transform infrared spectroscopy，FT-IR）、X射线粉末衍射法（X-ray diffraction，XRD）等手段表征了DM-β-CD与Lut形成的复合物，采用分子对接与分子动力学推测了复合物结构。结果 5种环糊精中DM-β-CD具有对Lut的最佳增溶作用，在浓度为2.5×10^-3 mol·L^-1时，Lut溶解度为1.56×10^-4 mol·L^-1，是纯水中溶解度的6.37倍；FT-IR与XRD表征了DM-β-CD/Lut复合物结构，主客体之存在弱相互作用；分子对接结果显示在复合物中，Lut的中A环与C环复合在DM-β-CD空腔中，B环位于DM-β-CD的大口处，主客体之间存在多个氢键作用；分子动力学模拟显示DM-β-CD/Lut复合物在5 ns内结构稳定，未发生较大形变，主、客体均方根差分别为2.632 0与0.475 4Å。结论 DM-β-CD可有效提高Lut溶解度，增溶作用机理是二者之间形成了复合物。

Abstract:

OBJECTIVE To research solubility enhancement of luteolin(Lut) by 5 cyclodextrin and to investigate solubility enhancement mechanism of cyclodextrin on insoluble drugs. METHODS The technique of phase solubility was adopted to compare solubility enhancement effect of Lut by β-cyclodextrin(β-CD), γ-cyclodextrin, heptakis-(2-hydroxypropyl)-β- cyclodextrin, heptakis-(2,6-dimethyl)-β-cyclodextrin(DM-β-CD) and 6-glucosyl-β-cyclodextrin. Fourier transform infrared spectroscopy(FT-IR) and X-ray diffraction(XRD) were used to characterize the complex formed by DM-β-CD and Lut. Molecular docking and molecular dynamics simulation were applied to speculate the structure of complex. RESULTS The result of phase solubility experimentalindicated DM-β-CD had the maximum solubility enhancement effect to Lut among the above five cyclodextrins. When the concentration of DM-β-CD reached 2.5×10^-3 mol·L^-1, the solubility of Lut was 1.56×10^-4 mol·L^-1, which was 6.37 times higher than it in pure water. The structure of DM-β-CD/Lut complex was characterized by FT-IR and XRD. The results showed that there existed week intermolecular interaction between DM-β-CD and Lut in the complex. The result of molecular docking indicated the ring A and C of Lut were complexed in the hydrophobic cavity of DM-β-CD, and the ring B was located at the larger rim of the cyclodextrin. There were several hydrogen bonding interactions between the host and the guest. The result of molecular dynamics simulationshowedthestructure was stable in 5 ns and no large structural deformation was observed. The root mean square deviation changed of the host and the guest were 2.632 0 and 0.475 4 Å, respectively. CONCLUSION DM-β-CD can effectively enchance the aquous solubility of Lut and the enhancement mechamism is due to the formation non-covalent complex between DM-β-CD and Lut.