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

Claire Coderch, Javier Klett, Antonio Morreale, J Fernando Díaz, Federico Gago

Departamento de Farmacología, Universidad de Alcalá, Edificio Medicina, Alcalá de Henares, Madrid, Spain.

ChemMedChem 2012 May

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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. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Citation

Claire Coderch, Javier Klett, Antonio Morreale, J Fernando Díaz, Federico Gago. Comparative binding energy (COMBINE) analysis supports a proposal for the binding mode of epothilones to β-tubulin. ChemMedChem. 2012 May;7(5):836-43