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

• Published in: Chemical biology & drug design 2017-12, Vol.90 (6), p.1247-1259
• Main Authors: Jiménez, Verónica A., Alderete, Joel B., Navarrete, Karen R.
• Format: Article
• Language: English
• Subjects: Binding Sites; bioactive conformation; Crystallography, X-Ray; Dimerization; epothilones; Epothilones - chemistry; Epothilones - metabolism; Ligands; Molecular Conformation; Molecular Dynamics Simulation; molecular modeling; Protein Binding; Protein Structure, Tertiary; protein–ligand interactions; Thermodynamics; Tubulin - chemistry; Tubulin - metabolism; Tubulin Modulators - chemistry; Tubulin Modulators - metabolism; tubulin‐binding agents
• ISSN: 1747-0277; 1747-0285
• DOI: 10.1111/cbdd.13046

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. The tubulin‐binding modes of 20 epothilone derivatives were studied from molecular dynamics simulations, revealing that active ligands share a common region of association and similar binding poses compared to epothilone A in the crystallographic model 4I50. Active ligands are also flexible molecules that can adopt their bound‐like conformations in aqueous solution, thus requiring low‐energy conformational rearrangements for an effective interaction with the protein receptor, unlike inactive ligands.