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首页> 外文期刊>The FEBS journal >The betaI/betaIII-tubulin isoforms and their complexes with antimitotic agents. Docking and molecular dynamics studies
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The betaI/betaIII-tubulin isoforms and their complexes with antimitotic agents. Docking and molecular dynamics studies

机译：betaI / betaIII-微管蛋白同工型及其与抗有丝分裂剂的复合物。对接和分子动力学研究

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Both microtubule destabilizer and stabilizer agents are important molecules in anticancer therapy. In particular, paclitaxel has been demonstrated to be effective for the treatment of ovarian, breast, and nonsmall cell lung carcinomas. It has been shown that emergence of resistance against this agent correlates with an increase in the relative abundance of tubulin isoform betaIII and that the more recently discovered IDN5390 can be effectively used once resistance has emerged. In this paper, we analyze the binding modes of these antimitotic agents to type I and III isoforms of beta-tubulin by computational methods. Our results are able to provide a molecular explanation of the experimental data. Using the same protocol, we could also show that no preference for any of the two isoforms can be detected for epothilone A, a potentially very interesting drug for which no data about the emergence of resistance is currently available. Our analysis provides structural insights about the recognition mode and the stabilization mechanism of these antimitotic agents and provides useful suggestions for the design of more potent and selective antimitotic agents.
机译：微管去稳定剂和稳定剂都是抗癌治疗中的重要分子。特别是，紫杉醇已被证明可有效治疗卵巢癌，乳腺癌和非小细胞肺癌。已经显示出对该试剂的抗性的出现与微管蛋白同种型βIII的相对丰度的增加相关，并且一旦抗性出现，就可以有效地使用更新发现的IDN5390。在本文中，我们通过计算方法分析了这些抗有丝分裂剂与β-微管蛋白的I型和III型同工型的结合模式。我们的结果能够为实验数据提供分子解释。使用相同的方案，我们还可以表明，对于埃坡霉素A（这可能是非常有趣的药物，目前尚无关于耐药性出现的数据），无法检测到对两种同工型的任何偏爱。我们的分析提供有关这些抗有丝分裂剂的识别模式和稳定机制的结构见解，并为设计更有效和选择性的抗有丝分裂剂提供有用的建议。

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