Structure-based prediction of drug distribution across the headgroup and core strata of a phospholipid bilayer using surrogate phases.
Structure-based prediction of drug distribution across the headgroup and core strata of a phospholipid bilayer using surrogate phases.
复制标题
使用替代相基于结构预测药物在磷脂双层头基和核心层的分布。
DOI：
10.1021/mp5003366
复制
发表时间：
2014
影响因子：
4.9
通讯作者：
Balaz,Stefan
中科院分区：
文献类型：
--
作者：
Natesan,Senthil;Lukacova,Viera;Peng,Ming;Subramaniam,Rajesh;Lynch,Sandra;Wang,Zhanbin;Tandlich,Roman;Balaz,Stefan
药物在磷脂双层的核心（C）和头基（H）层中的溶剂化影响其生理转运速率和蓄积。这些特征，特别是整个双层层的完整药物分布曲线，通过实验获得是繁琐的，以至于即使简化的优选位置也仅可用于几十种化合物。最近，我们发现水合二乙酰磷脂酰胆碱（DAcPC）和正十六烷（C16）系统的分配系数（P）值（作为由最丰富的哺乳动物磷脂PC组成的双层的H-和C-层的替代物）与化合物的优选双层位置非常一致。高P值是典型的亲脂性聚集在核心，和低P值的特征，亲头的喜欢的头基。这种简单的模式并不适用于大多数化合物，它们通常具有更均匀的分布，也可能在H/C界面处积累。为了模拟完全分布，需要双层中每个药物状态的溶剂化能的相关性：（1）对于H层，它是DAcPC/WP值，计算为C16/W和C16/DAcPC的比率（2）C层：C_（16）/WP值;（3）对于H/C界面，用嵌在H层和C层中的分子片段DAcPC/W和C_（16）/W溶剂化参数表征了所有可能分子位姿的P值，分别的相关性，每个缩放两个Collander系数，被用于一个非线性的，基于质量平衡的模型内双层分布，这是适用于容易测量的overallP值的化合物在DMPC（M =肉豆蔻酰）双层和单层作为因变量。107中性化合物的校准模型解释了94%的实验方差，实现了类似的交叉验证水平，并同意与非平凡的，实验确定的双层位置为27种化合物。由此产生的基于结构的预测系统的双分子层内分布将有助于更现实的建模被动运输和药物与那些完整的膜蛋白，其中具有位于双分子层中的结合位点，如一些酶，流入和流出转运蛋白，和受体的相互作用。如果仅关注总体双层累积，则1-辛醇/WP值足以模拟研究集。
Solvation of drugs in the core (C) and headgroup (H) strata of phospholipid bilayers affects their physiological transport rates and accumulation. These characteristics, especially a complete drug distribution profile across the bilayer strata, are tedious to obtain experimentally, to the point that even simplified preferred locations are only available for a few dozen compounds. Recently, we showed that the partition coefficient (P) values in the system of hydrated diacetyl phosphatidylcholine (DAcPC) andn-hexadecane (C16), as surrogates of the H- and C-strata of the bilayer composed of the most abundant mammalian phospholipid, PC, agree well with the preferred bilayer location of compounds. HighPvalues are typical for lipophiles accumulating in the core, and lowPvalues are characteristic of cephalophiles preferring the headgroups. This simple pattern does not hold for most compounds, which usually have more even distribution and may also accumulate at the H/C interface. To model complete distribution, the correlates of solvation energies are needed for each drug state in the bilayer: (1) for the H-stratum it is the DAcPC/WPvalue, calculated as the ratio of the C16/W and C16/DAcPC (W for water)Pvalues; (2) for the C-stratum, the C16/WPvalue; (3) for the H/C interface, thePvalues for all plausible molecular poses are characterized using the fragment DAcPC/W and C16/W solvation parameters for the parts of the molecule embedded in the H- and C-strata, respectively. The correlates, each scaled by two Collander coefficients, were used in a nonlinear, mass-balance based model of intrabilayer distribution, which was applied to the easily measurable overallPvalues of compounds in the DMPC (M = myristoyl) bilayers and monolayers as the dependent variables. The calibrated model for 107 neutral compounds explains 94% of experimental variance, achieves similar cross-validation levels, and agrees well with the nontrivial, experimentally determined bilayer locations for 27 compounds. The resulting structure-based prediction system for intrabilayer distribution will facilitate more realistic modeling of passive transport and drug interactions with those integral membrane proteins, which have the binding sites located in the bilayer, such as some enzymes, influx and efflux transporters, and receptors. If only overall bilayer accumulation is of interest, the 1-octanol/WPvalues suffice to model the studied set.