Studies of (-)-pironetin binding to α-tubulin: conformation, docking, and molecular dynamics.
A comprehensive conformational analysis for the anticancer agent pironetin (1) was achieved by molecular modeling using density functional theory calculations at the B3PW91/DGTZVP level in combination with calculated and experimental (1)H-(1)H coupling constants comparison. Two solvent-dependent conformational families (L and M) were revealed for the optimum conformations. Docking studies of the pironetin-tubulin complex determined a quantitative model for the hydrogen-bond interactions of pironetin through the αAsn249, αAsn258, and αLys352 amino groups in α-tubulin, which supported the formation of a covalent adduct between the αLys352 and the β carbon atom of the α,β-unsaturated lactone. Saturation-transfer difference NMR spectroscopy confirmed that pironetin binds to tubulin, while molecular dynamics exposed a distortion of the tubulin secondary structure at the H8 and H10 α-helices as well as at the S9 β-sheet, where αLys352 is located. A large structural perturbation in the M-loop geometry between the αIle274 and αLeu285 residues, an essential region for molecular recognition between α-α and β-β units of protofilaments, was also identified and provided a rationale for the pironetin inhibitory activity.
Departamento de Química y Programa de Posgrado en Farmacología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional , A. P. 14-740, México D. F. 07000, Mexico.
Angel E
AE
Bañuelos-Hernández
José Alberto
JA
Mendoza-Espinoza
Rogelio
R
Pereda-Miranda
Carlos M
CM
Cerda-García-Rojas
D000970:Antineoplastic Agents / Q000737:chemistry*; D001665:Binding Sites; D008958:Models, Molecular; D008968:Molecular Conformation; D011753:Pyrones / Q000737:chemistry*; D011789:Quantum Theory; D013237:Stereoisomerism; D014404:Tubulin / Q000737:chemistry*
D000970:Antineoplastic Agents; D011753:Pyrones; D014404:Tubulin; C088446:pironetin