环糊精(CD)可通过将药物化合物包封在它们的腔内而增强药物化合物的稳定性和生物利用度。本研究利用分子动力学模拟来研究氢化可的松(HC)与各种甲基化CD衍生物之间的相互作用机制。结果表明,根据甲基化的程度和位置,HC加载到CD腔中遵循不同的机制。βCD和6-MeβCD的加载更完整,HC的羟基面向伯羟基边缘(PHR),酮侧面向仲羟基边缘(SHR)。相比之下,2,3-D-MeβCD和2,6-D-MeβCD表现出不同的负载机制,酮侧面向PHR,羟基面向SHR。均方根波动(RMSF)分析表明,甲基化增加了CD重原子的灵活性,3-MeβCD和2,3-D-MeβCD表现出最高的柔韧性。然而,纳入HC后,3-MeβCD,2,3-D-MeβCD,2-MeβCD,和6-MeβCD显示的灵活性显著降低,建议一个更刚性的结构,有效地将HC保留在他们的腔内。径向分布函数显示,甲基化CD腔最内层的水分子数量显着减少,特别是在TMeβCD中,表明极性降低。HC的存在导致高能水分子的释放,为HC负荷创造更有利的条件。构象分析显示甲基化导致PHR面积部分减少,中间边缘的面积显著减少,SHR的面积显着减少。HC的负载增加了大多数衍生物中PHR的面积,在2,6-D-MeβCD和6-MeβCD中观察到最明显的增加。相互作用能和结合自由能的分析表明,HC与甲基化CD衍生物的结合在热力学上比与βCD的结合更有利。与6-MeβCD观察到的最强关联,2-MeβCD,和2,3-D-MeβCD。
Cyclodextrins (CDs) can enhance the stability and bioavailability of pharmaceutical compounds by encapsulating them within their cavities. This study utilized molecular dynamics simulations to investigate the interaction mechanisms between hydrocortisone (HC) and various methylated CD derivatives. The results reveal that the loading of HC into CD cavities follows different mechanisms depending on the degree and position of methylation. Loading into βCD and 6-MeβCD was more complete, with the hydroxyl groups of HC facing the primary hydroxyl rim (PHR) and the ketone side facing the secondary hydroxyl rim (SHR). In contrast, 2,3-D-MeβCD and 2,6-D-MeβCD showed a different loading mechanism, with the ketone side facing the PHR and the hydroxyl groups facing the SHR. The root mean square fluctuation (RMSF) analysis demonstrated that methylation increases the flexibility of CD heavy atoms, with 3-MeβCD and 2,3-D-MeβCD exhibiting the highest flexibility. However, upon inclusion of HC, 3-MeβCD, 2,3-D-MeβCD, 2-MeβCD, and 6-MeβCD showed a significant reduction in flexibility, suggesting a more rigid structure that effectively retains HC within their cavities. The radial distribution function revealed a significant reduction in the number of water molecules within the innermost layer of the methylated CD cavities, particularly in TMeβCD, indicating a decrease in polarity. The presence of HC led to the release of high-energy water molecules, creating more favorable conditions for HC loading. Conformational analysis showed that methylation caused a partial decrease in the area of the PHR, a significant decrease in the area of the middle rim, and a notable decrease in the area of the SHR. The loading of HC increased the area of the PHR in most derivatives, with the most pronounced increase observed in 2,6-D-MeβCD and 6-MeβCD. The analysis of interaction energies and binding free energies demonstrated that the binding of HC to methylated CD derivatives is thermodynamically more favorable than to βCD, with the strongest association observed for 6-MeβCD, 2-MeβCD, and 2,3-D-MeβCD.