Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky 40506, USA.
J Pharm Sci. 2011 Jun;100(6):2136-46. doi: 10.1002/jps.22441. Epub 2011 Jan 6.
Atomic-level molecular dynamics simulations of 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) bilayers containing small, amphiphilic, drug-like molecules were carried out to examine the influence of polar functionality on membrane partitioning and transport. Three related molecules (tyramine, phenethylamine, and 4-ethylphenol) were chosen to allow a detailed study of the isolated effects of the amine and hydroxyl functionalities on the preferred solute location, free energies of transfer, and the effect of combining both functional groups in a same molecule. Transfer free energy profiles (from water) generated from molecular dynamics (MD) simulations as a function of bilayer depth compared favorably to comparable experimental results. The simulations allowed the determination of the location of the barrier domain for permeability where the transfer free energy is highest and the preferred binding region at which the free energy is a minimum for each of the three solutes. Comparisons of the free energy profiles reveal that the hydrocarbon chain interior is the region most selective to chemical structure of different solutes because the free energies of transfer in that region vary to a significantly greater extent than in other regions of the bilayer. The contributions of the hydroxyl and amino groups to the free energies of solute transfer from water to the interfacial region were close to zero in both the MD simulations and experimental measurements. This suggests that the free energy decrease observed for solute transfer into the head group region occurs with minimal loss in solvation by hydrogen bonding to polar functional groups on the solute and is largely driven by hydrophobicity. Overall, the joint experimental and simulation studies suggest that the assumption of additivity of free energy contributions from multiple polar functional groups on the same molecule may hold for predictions of passive bilayer permeability coefficients providing that the groups are well isolated. However, this assumption does not hold for predictions of relative liposome-binding affinities.
采用原子级分子动力学模拟方法，研究了含有小的两亲性药物样分子的 1,2-二油酰基-sn-甘油-3-磷酸胆碱（DOPC）双层膜，以考察极性官能团对膜分配和传输的影响。选择了三种相关分子（酪胺、苯乙胺和 4-乙基苯酚），以便详细研究胺基和羟基官能团对溶质首选位置、自由能转移以及将两个官能团组合在同一分子中的影响。分子动力学（MD）模拟生成的从水中的自由能转移能谱（profile）与可比实验结果相当吻合。这些模拟允许确定渗透性的势垒区域的位置，其中自由能转移最高，并且对于三种溶质中的每一种，自由能最低的首选结合区域。对自由能能谱的比较表明，烃链内部是对不同溶质化学结构选择性最高的区域，因为在该区域内的自由能转移比双层膜的其他区域变化大得多。在 MD 模拟和实验测量中，羟基和氨基基团对溶质从水中向界面区域转移的自由能的贡献都接近零。这表明，观察到的溶质向头部基团区域转移的自由能降低是由于溶质与极性官能团氢键的溶剂化作用损失最小，主要是由疏水性驱动的。总体而言，联合实验和模拟研究表明，对于预测被动双层渗透率系数，同一分子上多个极性官能团的自由能贡献的加和性假设可能成立，前提是这些基团彼此充分隔离。但是，对于预测相对脂质体结合亲和力，该假设不成立。
