Binding modes of cabazitaxel with the different human β-tubulin isotypes: DFT and MD studies.

Abstract

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 (- 29.5kcal/mol) and of paclitaxel on βIIa-tubulin (- 25.5kcal/mol) are much stronger than their effects on βIII-tubulin (- 17.8kcal/mol and - 8.6kcal/mol, respectively). However, the effect of cabazitaxel on βIII-tubulin (- 23.0kcal/mol) is comparable with that on βI-tubulin (- 24.0kcal/mol) and βIIa-tubulin (- 25.9kcal/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.