Do Zebrafish Obey Lipinski Rules?
Do Zebrafish Obey Lipinski Rules?
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DOI：
10.1021/acsmedchemlett.9b00063
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发表时间：
2019-06-01
影响因子：
4.2
通讯作者：
Huryn, Donna M.
中科院分区：
文献类型：
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作者：
Long, Keith;Kostman, Stephen J.;Huryn, Donna M.
在整个生物体表型测定中使用斑马鱼已经成为整个药物发现过程中的有价值的策略。斑马鱼检测不仅可用于在最早阶段筛选化合物库，还可用于评估高级先导化合物对特定生物途径的影响或毒性。然而，当在斑马鱼测定中遇到化合物的无活性时，几乎没有数据可用于判断化合物是否真正具有生物学惰性或由于缺乏对模型生物体的渗透性而无活性。虽然药物化学原理提出了预测人体口服生物利用度、细胞渗透性甚至细菌渗透性的参数，但尚未开发用于斑马鱼吸收的此类参数。为了解决这个问题，我们汇编了一组文献中报道的700种化合物，这些化合物在斑马鱼试验中具有活性，评估了它们的特性，并将它们与一组历史药物和一组最近批准的口服药物的特性进行了比较。虽然有些属性重叠，平均值和第10次和第90次的分子量，辛醇-水分配系数（logP），氢键计数，和极性表面积的斑马鱼活性化合物是统计学上不同的已知药物。这种分析应该是有用的科学家解释结构活性关系的基础上，从斑马鱼的测定数据，并帮助通知从鱼类到哺乳动物的翻译。
The use of zebrafish in whole organism phenotypic assays has become a valuable strategy throughout the drug discovery process. Zebrafish assays can be used not only to screen libraries of compounds at the earliest stages but also to evaluate advanced leads for their effects on specific biological pathways or for toxicity. However, when confronted with inactivity of a compound in a zebrafish assay, there are little data that can be used to judge if the compound is truly biologically inert or inactive due to a lack of permeability into the model organism. While medicinal chemistry principles suggest parameters that are predictive of human oral bioavailability, cellular permeability, and even bacterial permeability, there have been no such parameters developed for zebrafish absorption. To address this question, we compiled a set of 700 compounds reported in the literature to be active in zebrafish assays, evaluated their properties, and compared them to properties derived from a set of historical drugs and a set of recently approved oral drugs. While some properties overlap, the averages and 10th and 90th percentiles of molecular weight, octanol water partition coefficient (logP), H-bond counts, and polar surface area for zebrafish-active compounds are statistically different from those of known drugs. This analysis should be useful to scientists interpreting structure activity relationships based on data from zebrafish assays and help to inform the translation from fish to mammals.