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

Abstract

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. © 2023 Elsevier Inc.