化学
生物信息学
药品
中枢神经系统
分数(化学)
体外
透析
色谱法
数量结构-活动关系
联营
药物发现
计算生物学
药理学
生物化学
立体化学
神经科学
内科学
生物
基因
人工智能
医学
计算机科学
作者
Hong Wan,Mikael Rehngren,Fabrizio Giordanetto,Fredrik Bergström,Anders Tunek
摘要
A high-throughput method for rapid screening of in vitro drug-brain homogenate binding is presented. The method is based on a straightforward sample pooling approach combining equilibrium dialysis with liquid chromatography mass spectrometry (LCMS). A strong correlation of fraction unbound in brain (fu) between single compound measurements and 25-pooled compounds (R2 = 0.906) was obtained for a selection of structurally diverse CNS compounds with a wide range of fractions unbound. Effects of brain homogenate dilution and dialysis time were investigated. To the best of our knowledge, it was the first time that we have demonstrated consistent fraction unbound in mouse and rat brain homogenate, revealing the drug-tissue partitioning mechanism predominated by hydrophobic interaction. On the basis of this finding, a generic approach to estimate drug binding to various tissues is proposed. A robust and interpretable QSAR for fu prediction is also presented by statistical modeling.
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