Comparative binding energy (COMBINE) analysis supports a proposal for the binding mode of epothilones to β-tubulin

ChemMedChem. 2012 May;7(5):836-43. doi: 10.1002/cmdc.201200065. Epub 2012 Mar 16.


The conformational preferences of epothilone A (EPA) and a 12,13-cyclopropyl C12-epimerized analogue were explored in aqueous solution using molecular dynamics simulations. The simulated conformers that provided an optimal fit in the paclitaxel binding site of mammalian β-tubulin were then selected. The resulting modeled complexes were simulated before and after refinement of the M-loop to improve the fitting and assess ligand stability within the binding pocket. The tubulin-bound conformation of EPA was found to be unlike a previously reported solution obtained through mixed crystallographic/NMR/modeling studies. However, our conformation was in agreement with an NMR-based proposal although the exact binding pose within the site was different. Molecular models were built for the complexes of 14 epothilone derivatives with β-tubulin. A projection to latent structures regression method succeeded in providing a good prediction of the experimentally measured binding enthalpies for the whole set of ligands by assigning weights to a selection of interaction energy terms. These receptor-based, quantitative structure-activity relationships support the proposed binding mode, help confirm and interpret previously acquired experimental data, shed additional light on the effect of several β-tubulin mutations on ligand binding, and can potentially direct further experimental studies.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Epothilones / chemistry
  • Epothilones / metabolism*
  • Models, Molecular
  • Paclitaxel / chemistry
  • Paclitaxel / metabolism
  • Quantitative Structure-Activity Relationship
  • Thermodynamics
  • Tubulin / chemistry
  • Tubulin / metabolism*


  • Epothilones
  • Tubulin
  • Paclitaxel