PDF(Pubmed)
Abstract：
Theoretical predictions of the solubilizing capacity of micelles and vesicles present in intestinal fluid are important for the development of new delivery techniques and bioavailability improvement. A balance between accuracy and computational cost is a key factor for an extensive study of numerous compounds in diverse environments. In this study, we aimed to determine an optimal molecular dynamics (MD) protocol to evaluate small-molecule interactions with micelles composed of bile salts and phospholipids. MD simulations were used to produce free energy profiles for three drug molecules (danazol, probucol, and prednisolone) and one surfactant molecule (sodium caprate) as a function of the distance from the colloid center of mass. To address the challenges associated with such tasks, we compared different simulation setups, including freely assembled colloids versus pre-organized spherical micelles, full free energy profiles versus only a few points of interest, and a coarse-grained model versus an all-atom model. Our findings demonstrate that combining these techniques is advantageous for achieving optimal performance and accuracy when evaluating the solubilization capacity of micelles. All-atom (AA) and coarse-grained (CG) umbrella sampling (US) simulations and point-wise free energy (FE) calculations were compared to their efficiency to computationally analyze the solubilization of active pharmaceutical ingredients in intestinal fluid colloids.
摘要：
对存在于肠液中的胶束和囊泡的增溶能力的理论预测对于开发新的递送技术和生物利用度的改善是重要的。准确性和计算成本之间的平衡是在不同环境中广泛研究众多化合物的关键因素。在这项研究中,我们旨在确定最佳分子动力学(MD)方案,以评估小分子与由胆汁盐和磷脂组成的胶束的相互作用.MD模拟用于产生三种药物分子的自由能曲线(达那唑，普罗布考,和泼尼松龙）和一个表面活性剂分子（癸酸钠）作为距胶体质心距离的函数。为了应对与此类任务相关的挑战，我们比较了不同的模拟设置，包括自由组装的胶体和预先组织的球形胶束，完全自由能量曲线与只有几个兴趣点，以及粗粒度模型和全原子模型。我们的发现表明，当评估胶束的溶解能力时，结合这些技术对于实现最佳性能和准确性是有利的。将全原子（AA）和粗粒（CG）伞形采样（US）模拟和逐点自由能（FE）计算与其效率进行比较，以计算分析活性药物成分在肠液胶体中的溶解。
