Molecular Dynamics and Tubulin Polymerization Kinetics Study on 1,14-Heterofused Taxanes: Evidences of Stabilization of the Tubulin Head-to-Tail Dimer-Dimer Interaction

The effects on tubulin dynamics of paclitaxel, ortataxel and two recently developed taxol derivatives bearing a five-membered heterocyclic ring fused at the 1,14 position were analysed by means of molecular dynamic simulations and MMPBSA approach. Tubulin polymerization kinetics and microtubule morphology assays were also conducted, providing support to computational results. In particular, it has been shown that the two recently developed 1,14-heterofused taxanes IDN5839 and IDN5798 are able to speed up the in vitro tubulin assembly by promoting the nucleation phase and to affect microtubule network in cell earlier than paclitaxel.