Zhao Yuqi, Wang Jingwen, Wang Yanjie, Huang Jingfei
State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, 32, Eastern Jiaochang Road, Kunming, Yunnan, 650223, China.
J Clin Bioinforma. 2012 May 1;2(1):10. doi: 10.1186/2043-9113-2-10.
Mouse is widely used in animal testing of cardiovascular disease. However, a large number of cardiovascular drugs that have been experimentally proved to work well on mouse were withdrawn because they caused adverse side effects in human.
In this study, we investigate whether binding patterns of withdrawn cardiovascular drugs are conserved between mouse and human through computational dockings and molecular dynamic simulations. In addition, we also measured the level of conservation of gene expression patterns of the drug targets and their interacting partners by analyzing the microarray data.
The results show that target proteins of withdrawn cardiovascular drugs are functionally conserved between human and mouse. However, all the binding patterns of withdrawn drugs we retrieved show striking difference due to sequence divergence in drug-binding pocket, mainly through loss or gain of hydrogen bond donors and distinct drug-binding pockets. The binding affinities of withdrawn drugs to their receptors tend to be reduced from mouse to human. In contrast, the FDA-approved and best-selling drugs are little affected.
Our analysis suggests that sequence divergence in drug-binding pocket may be a reasonable explanation for the discrepancy of drug effects between animal models and human.
小鼠广泛应用于心血管疾病的动物试验。然而，大量在小鼠实验中被证明效果良好的心血管药物因在人体中产生不良副作用而被撤市。
在本研究中，我们通过计算对接和分子动力学模拟来研究撤市心血管药物在小鼠和人类之间的结合模式是否保守。此外，我们还通过分析微阵列数据来测量药物靶点及其相互作用伙伴的基因表达模式的保守程度。
结果表明，撤市心血管药物的靶蛋白在人类和小鼠之间功能保守。然而，我们检索到的撤市药物的所有结合模式均因药物结合口袋中的序列差异而表现出显著差异，主要是通过氢键供体的丢失或增加以及不同的药物结合口袋。撤市药物与其受体的结合亲和力往往从小鼠到人类逐渐降低。相比之下，美国食品药品监督管理局（FDA）批准的畅销药物受影响较小。
我们的分析表明，药物结合口袋中的序列差异可能是动物模型和人类药物效应差异的一个合理解释。
