Molecular dynamics and tubulin polymerization kinetics study on 1,14-heterofused taxanes: evidence 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 the MM-PBSA 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 the microtubule network in cells earlier than paclitaxel.
Dipartimento di Scienze Farmaceutiche - sezione di Chimica Generale e Organica "Alessandro Marchesini", Università degli Studi di Milano, via Venezian, 21 20133 Milano, Italy. alessandro.contini@unimi.it
Alessandro
A
Contini
Graziella
G
Cappelletti
Daniele
D
Cartelli
Gabriele
G
Fontana
Maria Luisa
ML
Gelmi
D001952:Bridged-Ring Compounds / Q000378:metabolism / Q000494:pharmacology; D045744:Cell Line, Tumor; D019295:Computational Biology; D006801:Humans; D007700:Kinetics; D061986:MCF-7 Cells; D008870:Microtubules / Q000737:chemistry / Q000648:ultrastructure; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D017239:Paclitaxel / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding; D011487:Protein Conformation; D055503:Protein Multimerization; D043823:Taxoids / Q000378:metabolism / Q000494:pharmacology*; D014404:Tubulin / Q000737:chemistry* / Q000378:metabolism*
D001952:Bridged-Ring Compounds; D043823:Taxoids; D014404:Tubulin; C404743:IDN 5109; D017239:Paclitaxel