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Comparative Binding Energy (COMBINE) Analysis Supports a Proposal for the Binding Mode of Epothilones to -Tubulin.
|Authors:||Coderch, Claire; Klett, Javier ; Morreale, Antonio ; Díaz, José Fernando ; Gago, Federico|
molecular dynamic simulations
|Citation:||ChemMedChem, 7 (5) : 836-843 (2012)|
|Abstract:||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|
|Description:||8 páginas, 4 figuras, 3 tablas -- PAGS nros. 836-843|
|Publisher version (URL):||http://dx.doi.org/ 10.1002/cmdc.201200065|
|Appears in Collections:||(CIB) Artículos|
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