Conformation and energy investigation of microtubule longitudinal dynamic instability induced by natural products

Area of Science:

• Pharmacology
• Biophysics
• Computational Chemistry

Background:

• Microtubule targeting agents (MTAs) like plinabulin, docetaxel, and vinblastine are crucial in cancer therapy.
• Their precise mechanisms on microtubule polymerization dynamics remain incompletely understood.
• Understanding these dynamics is key to optimizing current treatments and developing novel anticancer agents.

Purpose of the Study:

• To elucidate the conformational and energetic changes of microtubules during polymerization dynamics under the influence of plinabulin, docetaxel, and vinblastine.
• To investigate the synergistic effects of drug combinations on microtubule stability and dynamics.
• To provide a theoretical basis for developing new MTA-based cancer therapies.

Main Methods:

• Performed 140 nanoseconds of molecular dynamic simulations on seven tubulin models.
• Utilized binding free energy calculations to assess drug interactions.
• Validated computational findings using in vitro tubulin assembly assays.

Main Results:

• Plinabulin, docetaxel, and vinblastine disrupt microtubule polymerization by altering tubulin conformation and binding energies.
• The plinabulin-docetaxel combination destabilizes microtubules through MT bending and reduced polymerization polarity.
• The docetaxel-vinblastine combination synergistically enhances microtubule depolymerization and bending.

Conclusions:

• The study provides a detailed understanding of the molecular mechanisms of MTAs and their combinations.
• Findings offer theoretical guidance for novel MTA combinations in cancer treatment.
• This research promotes the optimized use of MTAs and aids in the development of new anticancer drugs.