School of Biomedical Engineering and Technology, Tianjin Medical University, 22 Qixiangtai Road, Tianjin, 300070, China.
Hefei National Laboratory of Physical Sciences at the Microscale, University of Science and Technology of China, Hefei, 230026, Anhui, China.
J Mol Model. 2020 May 30;26(6):162. doi: 10.1007/s00894-020-04400-w.
Taxanes (paclitaxel, docetaxel, cabazitaxel) are anticancer drugs as microtubule inhibitors. Following our previous studies on paclitaxel and docetaxel, in this work, we examine cabazitaxel and compare these three taxenes. The binding interaction of three taxanes with various β-tubulin isotypes is studied by homology modeling, molecular docking, and molecular dynamics simulations. The results show that the effects of docetaxel on βI-tubulin (- 29.5 kcal/mol) and of paclitaxel on βIIa-tubulin (- 25.5 kcal/mol) are much stronger than their effects on βIII-tubulin (- 17.8 kcal/mol and - 8.6 kcal/mol, respectively). However, the effect of cabazitaxel on βIII-tubulin (- 23.0 kcal/mol) is comparable with that on βI-tubulin (- 24.0 kcal/mol) and βIIa-tubulin (- 25.9 kcal/mol), consistent with the fact that overexpression of βIII-tubulin increases the drug resistance to paclitaxel and docetaxel, but has little influence for cabazitaxel. This theoretical research supports the use of cabazitaxel for patients who are resistant to the action of paclitaxel and docetaxel.
紫杉烷类（紫杉醇、多西他赛、卡巴他赛）是作为微管抑制剂的抗癌药物。在我们之前对紫杉醇和多西他赛的研究基础上，本工作研究了卡巴他赛并对这三种紫杉烷类进行了比较。通过同源建模、分子对接和分子动力学模拟研究了三种紫杉烷类与各种β-微管蛋白亚型的结合相互作用。结果表明，多西他赛对βI-微管蛋白（-29.5 kcal/mol）和紫杉醇对βIIa-微管蛋白（-25.5 kcal/mol）的作用远强于它们对βIII-微管蛋白（-17.8 kcal/mol 和-8.6 kcal/mol）的作用。然而，卡巴他赛对βIII-微管蛋白（-23.0 kcal/mol）的作用与对βI-微管蛋白（-24.0 kcal/mol）和βIIa-微管蛋白（-25.9 kcal/mol）的作用相当，这与βIII-微管蛋白过表达增加紫杉醇和多西他赛耐药性的事实一致，但对卡巴他赛影响不大。这一理论研究支持将卡巴他赛用于对紫杉醇和多西他赛作用产生耐药性的患者。
