Systematic profiling of taxol and its analogues (taxalogues) binding to -tubulin and molecular analysis of their effects on microtubule stabilization

Microtubules are highly dynamic polymers of alpha/beta-tubulin that represent major components of the cytoskeleton and have been established as an attractive drug gable target of tumors. Taxol, also known as Paclitaxel, is a microtubule-stabilizing agent that binds stoichiometrically to a specific site in beta-tubulin, where is out of but nearby the interacting interface of alpha/beta-tubulin complex, to improve the complex stability through an allosterically regulatory mechanism. In this study, the systematic binding profile of taxol and its 22 structurally diverse, medicinally relevant analogues (termed as taxalogues) to the specific site of beta-tubulin as well as their effects on the alpha/beta-tubulin complex stability were created and investigated by using structural modeling, dynamics simulation, and energetics analysis. Two helices H1 and H2 of beta-tubulin were identified as key hotspots at the alpha/beta-tubulin interface to mediate the binding event of beta-tubulin to alpha-tubulin. Taxalogue binding can trigger a conformational displacement in the H1 and H2 to elicit the stabilization (or destabilization) of alpha/beta-tubulin. However, strong taxalogue binding potency to beta-tubulin does not mean effective alpha/beta-tubulin stabilization; there is only an indirect, moderate correlation between them. Cell viability assay revealed that the taxalogue-induced alpha/beta-tubulin stabilization, but not the taxalogue binding, directly influences the antitumor activity of taxalogues. The activity increases in the order: SB-T-1214 < docetaxel < taxol < larotaxel < cisplatin < cabazitaxel.