title: Comparative binding energy (COMBINE) analysis supports a proposal for the binding mode of epothilones to β-tubulin.
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.
authors.affiliation: Departamento de Farmacología, Universidad de Alcalá, Edificio Medicina, Alcalá de Henares, Madrid, Spain.
authors.forename: Claire
authors.initials: C
authors.lastname: Coderch
authors.forename: Javier
authors.initials: J
authors.lastname: Klett
authors.forename: Antonio
authors.initials: A
authors.lastname: Morreale
authors.forename: J
authors.initials: J
authors.lastname: Fernando Díaz
authors.forename: Federico
authors.initials: F
authors.lastname: Gago
mesh_terms: D001665:Binding Sites; D034261:Epothilones / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D017239:Paclitaxel / Q000737:chemistry / Q000378:metabolism; D021281:Quantitative Structure-Activity Relationship; D013816:Thermodynamics; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism*
chemical_list: D034261:Epothilones; D014404:Tubulin; D017239:Paclitaxel