School of Chemistry, National University of Ireland-Galway, Galway, Ireland.
J Chem Theory Comput. 2011 Mar 8;7(3):560-74. doi: 10.1021/ct100528u. Epub 2011 Jan 28.
The promising photosensitizing properties of hypericin, a natural quinine substituted with hydroxyl and alkyl groups, have led to the proposal that it can be utilized in photodynamic therapy. Neither the detailed mechanism behind the powerful action of hypericin, arising as a result of light excitation, nor the intracellular localization and transportation of the molecule is yet fully understood. The behavior of hypericin derivatives in a pure dipalmitoylphosphatidylcholine (DPPC) lipid membrane has recently been studied theoretically by means of molecular dynamics simulations. Natural membranes however contain many important constituents-cholesterol being one of the most essential-that influence the function and structure of the membrane, and thereby also the behavior of drug molecules therein. In the present study, we investigated hypericin and its brominated derivatives in membranes containing 9 and 25 mol % cholesterol. The results show that the presence of cholesterol in the membrane affects the permeability of the hypericin molecules and does so differently for the various molecules in the two membranes. Hypericin containing one bromine was found to exhibit the lowest free energy profile for the transport process into the lipids, and also the highest permeability coefficients, indicating that this molecule displays the fastest and easiest diffusion in the membranes. All three molecules were found to accumulate most preferably close to the polar headgroup region in both membranes.
作为一种天然的奎宁类药物，金丝桃素的羟基和烷基取代基赋予了其很有前景的光敏特性，这使得人们提出可以将其应用于光动力疗法。无论是由于光激发而产生的金丝桃素强大作用的详细机制，还是该分子的细胞内定位和运输，都尚未完全了解。最近，通过分子动力学模拟的方法对纯二棕榈酰磷脂酰胆碱（DPPC）脂质膜中金丝桃素衍生物的行为进行了理论研究。然而，天然膜中含有许多重要的成分——胆固醇是其中最重要的成分之一——这些成分会影响膜的功能和结构，从而也会影响膜中药物分子的行为。在本研究中，我们研究了含有 9 和 25 摩尔%胆固醇的膜中的金丝桃素及其溴代衍生物。结果表明，胆固醇在膜中的存在会影响金丝桃素分子的通透性，并且在两种膜中的不同分子中影响方式也不同。在含有一个溴原子的金丝桃素的情况下，发现其在向脂质中运输的过程中具有最低的自由能曲线，并且具有最高的渗透率系数，这表明该分子在膜中显示出最快和最容易的扩散。在两种膜中，所有三种分子都被发现最优选地积聚在极性头部基团区域附近。
