Molecular modeling study on the tubulin-binding modes of epothilone derivatives: Insight into the structural basis for epothilones activity

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

Resultado de la investigación: Article

2 Citas (Scopus)

Resumen

Molecular dynamics (MD) simulations were employed to study the tubulin-binding modes of 20 epothilone derivatives spanning a wide range of antitumor activity. Trajectory analysis revealed that active ligands shared a common region of association and similar binding poses compared to the high-resolution crystal structure of the tubulin complex with epothilone A, the stathmin-like protein RB3, and tubulin tyrosine ligase (PDB code 4I50). Conformational analysis of epothilones in aqueous solution and tubulin-bound states indicated that the bound conformations of active species can be found to a significant extent within the ensemble of conformers available in aqueous solution. On the other hand, inactive derivatives were unable to adopt bound-like conformations in aqueous solution, thus requiring an extensive conformational pre-organization to accomplish an effective interaction with the tubulin receptor. Additionally, MD results revealed that epothilone binding-induced structuring of the M-loop and local flexibility changes in protein regions involved in interdimeric contacts that are relevant for microtubule stabilization. These results provide novel, valuable structural information to increase understanding about the underlying molecular aspects of epothilones activity and support further work on the search for new active tubulin-binding agents.

Idioma originalEnglish
PublicaciónChemical Biology and Drug Design
DOI
EstadoAccepted/In press - 2017

Huella dactilar

Epothilones
Molecular modeling
Tubulin
Derivatives
Molecular Dynamics Simulation
Conformations
Molecular dynamics
Stathmin
Microtubules
Proteins
Stabilization
Crystal structure
Trajectories
Association reactions
Ligands
Computer simulation

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

Citar esto

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title = "Molecular modeling study on the tubulin-binding modes of epothilone derivatives: Insight into the structural basis for epothilones activity",
abstract = "Molecular dynamics (MD) simulations were employed to study the tubulin-binding modes of 20 epothilone derivatives spanning a wide range of antitumor activity. Trajectory analysis revealed that active ligands shared a common region of association and similar binding poses compared to the high-resolution crystal structure of the tubulin complex with epothilone A, the stathmin-like protein RB3, and tubulin tyrosine ligase (PDB code 4I50). Conformational analysis of epothilones in aqueous solution and tubulin-bound states indicated that the bound conformations of active species can be found to a significant extent within the ensemble of conformers available in aqueous solution. On the other hand, inactive derivatives were unable to adopt bound-like conformations in aqueous solution, thus requiring an extensive conformational pre-organization to accomplish an effective interaction with the tubulin receptor. Additionally, MD results revealed that epothilone binding-induced structuring of the M-loop and local flexibility changes in protein regions involved in interdimeric contacts that are relevant for microtubule stabilization. These results provide novel, valuable structural information to increase understanding about the underlying molecular aspects of epothilones activity and support further work on the search for new active tubulin-binding agents.",
keywords = "Bioactive conformation, Epothilones, Molecular modeling, Protein-ligand interactions, Tubulin-binding agents",
author = "Jim{\'e}nez, {Ver{\'o}nica A.} and Alderete, {Joel B.} and Navarrete, {Karen R.}",
year = "2017",
doi = "10.1111/cbdd.13046",
language = "English",
journal = "Chemical Biology and Drug Design",
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T1 - Molecular modeling study on the tubulin-binding modes of epothilone derivatives

T2 - Insight into the structural basis for epothilones activity

AU - Jiménez, Verónica A.

AU - Alderete, Joel B.

AU - Navarrete, Karen R.

PY - 2017

Y1 - 2017

N2 - Molecular dynamics (MD) simulations were employed to study the tubulin-binding modes of 20 epothilone derivatives spanning a wide range of antitumor activity. Trajectory analysis revealed that active ligands shared a common region of association and similar binding poses compared to the high-resolution crystal structure of the tubulin complex with epothilone A, the stathmin-like protein RB3, and tubulin tyrosine ligase (PDB code 4I50). Conformational analysis of epothilones in aqueous solution and tubulin-bound states indicated that the bound conformations of active species can be found to a significant extent within the ensemble of conformers available in aqueous solution. On the other hand, inactive derivatives were unable to adopt bound-like conformations in aqueous solution, thus requiring an extensive conformational pre-organization to accomplish an effective interaction with the tubulin receptor. Additionally, MD results revealed that epothilone binding-induced structuring of the M-loop and local flexibility changes in protein regions involved in interdimeric contacts that are relevant for microtubule stabilization. These results provide novel, valuable structural information to increase understanding about the underlying molecular aspects of epothilones activity and support further work on the search for new active tubulin-binding agents.

AB - Molecular dynamics (MD) simulations were employed to study the tubulin-binding modes of 20 epothilone derivatives spanning a wide range of antitumor activity. Trajectory analysis revealed that active ligands shared a common region of association and similar binding poses compared to the high-resolution crystal structure of the tubulin complex with epothilone A, the stathmin-like protein RB3, and tubulin tyrosine ligase (PDB code 4I50). Conformational analysis of epothilones in aqueous solution and tubulin-bound states indicated that the bound conformations of active species can be found to a significant extent within the ensemble of conformers available in aqueous solution. On the other hand, inactive derivatives were unable to adopt bound-like conformations in aqueous solution, thus requiring an extensive conformational pre-organization to accomplish an effective interaction with the tubulin receptor. Additionally, MD results revealed that epothilone binding-induced structuring of the M-loop and local flexibility changes in protein regions involved in interdimeric contacts that are relevant for microtubule stabilization. These results provide novel, valuable structural information to increase understanding about the underlying molecular aspects of epothilones activity and support further work on the search for new active tubulin-binding agents.

KW - Bioactive conformation

KW - Epothilones

KW - Molecular modeling

KW - Protein-ligand interactions

KW - Tubulin-binding agents

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