Impact of species-dependent differences on screening, design, and development of MAO B inhibitors
Impact of species-dependent differences on screening, design, and development of MAO B inhibitors
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DOI：
10.1021/jm060441e
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发表时间：
2006-10-19
影响因子：
7.3
通讯作者：
Reist, Marianne
中科院分区：
文献类型：
--
作者：
Novaroli, Laura;Daina, Antoine;Reist, Marianne
人类和大鼠MAO B的物种依赖性差异对香豆素和5H-吲哚[1,2-c]吡嗪-5- 1衍生物两类化合物抑制剂筛选的影响得到了证实。所有检测的化合物都显示出对人MAO B的抑制作用大于对大鼠MAO B的抑制作用。此外，在人和大鼠之间没有发现pIC（50）值的相关性。这些差异对参与MAO B代谢途径的药物的设计和开发具有重要意义，这表明使用大鼠酶获得的结果不能先验地外推到人类中枢神经系统。事实上，用人类的酶和用大鼠的酶来选择产生铅的化合物可能会有所不同。此外，取代基对同质香豆素系列和5h - indo [1,2-c] pyridazin-5-one衍生物对人MAO B体外抑制的影响明显不同，表明不同的结合模式，抑制剂与人MAO B活性位点的分子对接模拟清楚地支持了这一假设。
The impact of species- dependent differences between human and rat MAO B on inhibitor screening was evidenced for two classes of compounds, coumarin and 5H- indeno[1,2-c] pyridazin-5-one derivatives. All examined compounds have shown a greater inhibitor potency toward human MAO B than toward rat MAO B. Moreover, no correlation was found between human and rat pIC(50) values. These divergences have important implications for the design and development of drugs involved in the MAO B metabolic pathway, suggesting that results obtained using rat enzyme cannot be extrapolated to human CNS, a priori. Indeed, the selection of a hit compound for lead generation could be different using human rather than rat enzyme. Moreover, the influence of substituents on the in vitro inhibition of human MAO B was markedly different between homogeneous series of coumarin and 5H-indeno[1,2-c] pyridazin-5-one derivatives, suggesting different binding modes, a hypothesis clearly supported by molecular docking simulations of inhibitors into the active site of human MAO B.