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

• 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 beta-tubulin isotypes is studied by homology modeling, molecular docking, and molecular dynamics simulations. The results show that the effects of docetaxel on beta I-tubulin (- 29.5 kcal/mol) and of paclitaxel on beta IIa-tubulin (- 25.5 kcal/mol) are much stronger than their effects on beta III-tubulin (- 17.8 kcal/mol and - 8.6 kcal/mol, respectively). However, the effect of cabazitaxel on beta III-tubulin (- 23.0 kcal/mol) is comparable with that on beta I-tubulin (- 24.0 kcal/mol) and beta IIa-tubulin (- 25.9 kcal/mol), consistent with the fact that overexpression of beta III-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.

Ämnesord

NATURVETENSKAP  -- Kemi (hsv//swe)

NATURAL SCIENCES  -- Chemical Sciences (hsv//eng)

Nyckelord

Cabazitaxel

beta-Tubulin isotypes

Taxenes

DFT methods

MD simulations

Drug resistance

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