Computation of brain-blood partitioning of organic solutes via free energy calculations
Computation of brain-blood partitioning of organic solutes via free energy calculations
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DOI：
10.1021/jm960163r
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发表时间：
1996-11-22
影响因子：
7.3
通讯作者：
Curatolo, WJ
中科院分区：
文献类型：
--
作者：
Lombardo, F;Blake, JF;Curatolo, WJ
从简单溶质到组胺 H-2 拮抗剂的一系列化合物的脑血分配比 log(C-brain/C-blood) (log BB) 与计算的水中溶剂化自由能 (Delta G 度 (W)) 相关。使用 AM1-SM2.1 溶剂化模型通过 AMSOL 5.0 程序计算自由能。从一组 55 种化合物中，开发了一个函数，其中 log BB 与溶剂化自由能的关系如下：log BB = 0.054 Delta G 度(W) + 0.43（r = 0.82，标准误差 = 0.41）。这种相关性成功地预测了训练数据集之外的化合物的脑血分配。此外，对于一组 10 种药物，Delta G 度 (W) 与牛脑微血管内皮细胞单层渗透性的文献数据密切相关。在神经科学药物发现中，使用计算的溶剂化自由能来预测大脑渗透提供了一种优先考虑合成靶点的简便方法。
The ratio of brain-blood partitioning, log(C-brain/C-blood) (log BB), of a series of compounds that range from simple solutes to histamine H-2 antagonists was correlated with computed solvation free energy in water(Delta G degrees(W)). The free energies were computed with the AMSOL 5.0 program using the AM1-SM2.1 solvation model. From a set of 55 compounds, a function was developed in which log BB was related to the free energy of solvation as follows: log BB = 0.054 Delta G degrees(W) + 0.43 (r = 0.82 and standard error = 0.41). This correlation provided successful prediction of brain-blood partitioning for compounds outside the training dataset. Furthermore, for a set of 10 drugs, Delta G degrees(W) correlated well with literature data for the permeability of endothelial cell monolayers from bovine brain microvessels. In neuroscience drug discovery, the use of computed solvation free energies to predict brain penetration provides a facile method for prioritizing synthetic targets.