Structural insight into epothilones antitumor activity based on the conformational preferences and tubulin binding modes of epothilones A and B obtained from molecular dynamics simulations

Verónica A. Jiménez, Joel B. Alderete, Karen R. Navarrete

Resultado de la investigación: Article

5 Citas (Scopus)

Resumen

Molecular dynamics simulations were employed to analyze the conformational preferences and binding modes of epothilones A and B as a source of structural information regarding the antitumor properties of these species. Our results suggest that the conformation of free and tubulin-bound epothilones is strongly influenced by the presence of a methyl group at C12 and that epothilones A and B exploit the binding cavity in a unique and different way. The binding sites of epothilones A and B share a common region of association (Leu215, Leu217, His227, Leu228, Ala231, Phe270, Gly360, and Leu361), but lead to different ligand-residue interactions. Average interaction energies predict a larger stabilization for the epothilone B-tubulin complex, which is mainly driven by the enhancement of the electrostatic component of ligand-residue interactions compared to the epothilone A-tubulin complex. These structural and energetic results can be useful to account for the activity difference between epothilones A and B, and to design more active and potent analogs that resemble the mechanism of action of epothilones against cancer cells.

Idioma originalEnglish
Páginas (desde-hasta)789-803
Número de páginas15
PublicaciónJournal of Biomolecular Structure and Dynamics
Volumen33
N.º4
DOI
EstadoPublished - 3 abr 2015

Huella dactilar

Epothilones
Molecular Dynamics Simulation
Tubulin
Ligands
Static Electricity
Binding Sites
epothilone B
epothilone A
Neoplasms

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

Citar esto

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abstract = "Molecular dynamics simulations were employed to analyze the conformational preferences and binding modes of epothilones A and B as a source of structural information regarding the antitumor properties of these species. Our results suggest that the conformation of free and tubulin-bound epothilones is strongly influenced by the presence of a methyl group at C12 and that epothilones A and B exploit the binding cavity in a unique and different way. The binding sites of epothilones A and B share a common region of association (Leu215, Leu217, His227, Leu228, Ala231, Phe270, Gly360, and Leu361), but lead to different ligand-residue interactions. Average interaction energies predict a larger stabilization for the epothilone B-tubulin complex, which is mainly driven by the enhancement of the electrostatic component of ligand-residue interactions compared to the epothilone A-tubulin complex. These structural and energetic results can be useful to account for the activity difference between epothilones A and B, and to design more active and potent analogs that resemble the mechanism of action of epothilones against cancer cells.",
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AU - Jiménez, Verónica A.

AU - Alderete, Joel B.

AU - Navarrete, Karen R.

PY - 2015/4/3

Y1 - 2015/4/3

N2 - Molecular dynamics simulations were employed to analyze the conformational preferences and binding modes of epothilones A and B as a source of structural information regarding the antitumor properties of these species. Our results suggest that the conformation of free and tubulin-bound epothilones is strongly influenced by the presence of a methyl group at C12 and that epothilones A and B exploit the binding cavity in a unique and different way. The binding sites of epothilones A and B share a common region of association (Leu215, Leu217, His227, Leu228, Ala231, Phe270, Gly360, and Leu361), but lead to different ligand-residue interactions. Average interaction energies predict a larger stabilization for the epothilone B-tubulin complex, which is mainly driven by the enhancement of the electrostatic component of ligand-residue interactions compared to the epothilone A-tubulin complex. These structural and energetic results can be useful to account for the activity difference between epothilones A and B, and to design more active and potent analogs that resemble the mechanism of action of epothilones against cancer cells.

AB - Molecular dynamics simulations were employed to analyze the conformational preferences and binding modes of epothilones A and B as a source of structural information regarding the antitumor properties of these species. Our results suggest that the conformation of free and tubulin-bound epothilones is strongly influenced by the presence of a methyl group at C12 and that epothilones A and B exploit the binding cavity in a unique and different way. The binding sites of epothilones A and B share a common region of association (Leu215, Leu217, His227, Leu228, Ala231, Phe270, Gly360, and Leu361), but lead to different ligand-residue interactions. Average interaction energies predict a larger stabilization for the epothilone B-tubulin complex, which is mainly driven by the enhancement of the electrostatic component of ligand-residue interactions compared to the epothilone A-tubulin complex. These structural and energetic results can be useful to account for the activity difference between epothilones A and B, and to design more active and potent analogs that resemble the mechanism of action of epothilones against cancer cells.

KW - Bioactive conformation

KW - epothilones

KW - molecular dynamics

KW - tubulin

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