Computational analysis of drug resistance of taxanes bound to human β-tubulin mutant (D26E)

Abdullahi Ibrahim Uba, Candice Bui-Linh, Julianne M. Thornton, Michael Olivieri, Chun Wu

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The single-point mutation D26E in human β-tubulin is associated with drug resistance seen with two anti-mitotic taxanes (paclitaxel and docetaxel) when used to treat cancers. The molecular mechanism of this resistance remains elusive. However, docetaxel and a third-generation taxane, cabazitaxel, are thought to overcome this resistance. Here, structural models of both the wildtype (WT) and D26E mutant (MT) human β-tubulin were constructed based on the crystal structure of pig β-tubulin in complex with docetaxel (PDB ID: 1TUB). The three taxanes were docked into the WT and MT β-tubulin, and the resulting complexes were submitted to three independent runs of 200 ns molecular dynamic simulations, which were then averaged. MM/GBSA calculations revealed the binding energy of paclitaxel with WT and MT β-Tubulin to be −101.5 ± 8.4 and −90.4 ± 8.9 kcal/mol, respectively. The binding energy of docetaxel was estimated to be −104.7 ± 7.0 kcal/mol with the WT and −103.8 ± 5.5 kcal/mol with the MT β-tubulin. Interestingly, cabazitaxel was found to have a binding energy of −122.8 ± 10.8 kcal/mol against the WT and −106.2 ± 7.0 kcal/mol against the MT β-tubulin. These results show that paclitaxel and docetaxel bound to the MT less strongly than the WT, suggesting possible drug resistance. Similarly, cabazitaxel displayed a greater binding propensity against WT and MT β-tubulin than the other two taxanes. Furthermore, the dynamic cross-correlation matrices (DCCM) analysis suggests that the single-point mutation D26E induces a subtle dynamical difference in the ligand-binding domain. Overall, the present study revealed how the single-point mutation D26E may reduce the binding affinity of the taxanes, however, the effect of the mutation does not significantly affect the binding of cabazitaxel.

Original languageEnglish (US)
Article number108503
JournalJournal of Molecular Graphics and Modelling
StatePublished - Sep 2023

All Science Journal Classification (ASJC) codes

  • Spectroscopy
  • Physical and Theoretical Chemistry
  • Computer Graphics and Computer-Aided Design
  • Materials Chemistry


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