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

Area of Science:

• Pharmacology
• Molecular Biology
• Computational Chemistry

Background:

• Taxanes (paclitaxel, docetaxel, cabazitaxel) are microtubule inhibitors used in cancer therapy.
• Previous studies focused on paclitaxel and docetaxel; this work investigates cabazitaxel's interactions.
• Overexpression of βIII-tubulin can confer resistance to paclitaxel and docetaxel.

Purpose of the Study:

• To compare the binding interactions of paclitaxel, docetaxel, and cabazitaxel with different β-tubulin isotypes.
• To investigate the molecular basis for cabazitaxel's efficacy in drug-resistant cancers.

Main Methods:

• Homology modeling was used to create structural models of β-tubulin isotypes.
• Molecular docking simulations predicted the binding affinities of taxanes to tubulin.
• Molecular dynamics simulations provided insights into the stability of taxane-tubulin complexes.

Main Results:

• Docetaxel and paclitaxel exhibited stronger binding to βI and βIIa-tubulin, respectively, compared to βIII-tubulin.
• Cabazitaxel demonstrated comparable binding affinities across βI, βIIa, and βIII-tubulin isotypes.
• The binding patterns explain why βIII-tubulin overexpression impacts resistance to paclitaxel and docetaxel but not cabazitaxel.

Conclusions:

• Cabazitaxel's binding profile suggests its potential utility in patients resistant to other taxanes.
• This theoretical research supports cabazitaxel as a treatment option for taxane-resistant malignancies.
• Understanding taxane-tubulin interactions at the molecular level aids in personalized cancer therapy.