TY - JOUR
T1 - 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
AU - Jiménez, Verónica A.
AU - Alderete, Joel B.
AU - Navarrete, Karen R.
N1 - Funding Information:
The authors thank FONDECYT Program for the support under [grant number 1120250].
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
UR - http://www.scopus.com/inward/record.url?scp=84922226067&partnerID=8YFLogxK
U2 - 10.1080/07391102.2014.911702
DO - 10.1080/07391102.2014.911702
M3 - Article
C2 - 24773261
AN - SCOPUS:84922226067
SN - 0739-1102
VL - 33
SP - 789
EP - 803
JO - Journal of Biomolecular Structure and Dynamics
JF - Journal of Biomolecular Structure and Dynamics
IS - 4
ER -