Elucidating the Mechanism of Action of the Clinically Approved Taxanes: A Comprehensive Comparison of Local and Allosteric Effects

The clinically approved taxanes (paclitaxel, docetaxel and cabazitaxel) target the tubulin protein in microtubules. Despite the clinical success of these agents, the mechanism of action of this class of drugs remains elusive, making rational design of taxanes difficult. Molecular dynamics simulations of these three taxanes with the alpha beta-tubulin heterodimer examine the similarities and differences in the effects of the drugs on tubulin, probing both local and allosteric effects. Despite their structural similarity, the drugs adopt different conformations in the binding site on beta-tubulin. The taxanes similarly increase the helical character of alpha- and beta-tubulins. No correlations are found between microtubule assembly and (i) binding affinity or (ii) the role of the M-loop in enhancing lateral contacts. Instead, changes in intra-and interdimer longitudinal contacts are indicative of the mechanism of action of the taxanes. We find beta:H1-S10, and more importantly beta: H9 and beta:H10, play a role translating the effect of local drug binding in beta-tubulin to an allosteric effect in alpha-tubulin and propose that the displacement of these secondary structures towards alpha-tubulin may be used as a predictor of the effect of taxanes on the tubulin heterodimers in rational drug design approaches.