Moghadam Soroush, Larson Ronald G
Department of Mechanical Engineering, University of Michigan , Ann Arbor, Michigan 48109-2136, United States.
Department of Chemical Engineering, University of Michigan , Ann Arbor, Michigan 48109-2136, United States.
Mol Pharm. 2017 Feb 6;14(2):478-491. doi: 10.1021/acs.molpharmaceut.6b00942. Epub 2017 Jan 11.
All-atom molecular dynamic simulations (AA-MD) are performed for aqueous solutions of hydrophobic drug molecules (phenytoin) with model polymer excipients, namely, (1) N-isopropylacrylamide, (pNIPAAm), (2) pNIPAAm-co-acrylamide (Am), and (3) pNIPAAm-co-dimethylacrylamide (DMA). After validating the force field parameters using the well-known lower critical solution behavior of pNIPAAm, we simulate the polymer-drug complex in water and its behavior at temperatures below (295 K) and above the LCST (310 K). Using radial distribution functions, we find that there is an optimum comonomer molar fraction of around 20-30% DMA at which interaction with phenytoin drug molecules is strongest, consistent with recent experimental findings. The results provide evidence that molecular simulations are able to provide guidance in the optimization of novel polymer excipients for drug release.
对疏水性药物分子（苯妥英）与模型聚合物辅料的水溶液进行了全原子分子动力学模拟（AA-MD），这些辅料分别为：（1）N-异丙基丙烯酰胺（pNIPAAm）、（2）pNIPAAm-共-丙烯酰胺（Am）以及（3）pNIPAAm-共-二甲基丙烯酰胺（DMA）。在用pNIPAAm众所周知的低临界溶解行为验证力场参数之后，我们模拟了聚合物-药物复合物在水中的情况及其在低于（295 K）和高于最低临界溶液温度（310 K）时的行为。使用径向分布函数，我们发现存在一个约20-30% DMA的最佳共聚单体摩尔分数，在该分数下与苯妥英药物分子的相互作用最强，这与最近的实验结果一致。结果表明分子模拟能够为新型聚合物辅料用于药物释放的优化提供指导。
