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.
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.
a Facultad de Ciencias Exactas, Departamento de Ciencias Químicas , Universidad Andres Bello Sede Concepción , Autopista Concepción-Talcahuano, 7100 Talcahuano , Chile.
Verónica A
VA
Jiménez
Joel B
JB
Alderete
Karen R
KR
Navarrete
D000970:Antineoplastic Agents / Q000737:chemistry*; D001665:Binding Sites; D034261:Epothilones / Q000737:chemistry*; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D014404:Tubulin / Q000737:chemistry*; D050257:Tubulin Modulators / Q000737:chemistry*
D000970:Antineoplastic Agents; D034261:Epothilones; D014404:Tubulin; D050257:Tubulin Modulators; C093787:epothilone A; C093788:epothilone B
bioactive conformation; epothilones; molecular dynamics; tubulin