Studies of (-)-pironetin binding to a-tubulin: Conformation, docking, and molecular dynamics
Por:
Banuelos-Hernandez, AE, Mendoza-Espinoza J.A., Pereda-Miranda R., Cerda-García-Rojas C.M.
Publicada:
2 may 2014
Categoría:
Organic Chemistry
Resumen:
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 1H-1H 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 aAsn249, aAsn258, and aLys352 amino groups in a-tubulin, which supported the formation of a covalent adduct between the aLys352 and the ß carbon atom of the a,ß-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 a-helices as well as at the S9 ß-sheet, where aLys352 is located. A large structural perturbation in the M-loop geometry between the aIle274 and aLeu285 residues, an essential region for molecular recognition between a-a and ß-ß units of protofilaments, was also identified and provided a rationale for the pironetin inhibitory activity. © 2014 American Chemical Society.
Filiaciones:
Mendoza-Espinoza J.A.:
Departamento de Química y Programa de Posgrado en Farmacología, Centro de Investigación y de Estudios Avanzados, Instituto Politécnico Nacional, A. P. 14-740, México D. F. 07000, Mexico
Pereda-Miranda R.:
Univ Nacl Autonoma Mexico, Fac Quim, Dept Farm, Mexico City 04510, DF, Mexico
Cerda-García-Rojas C.M.:
Departamento de Química y Programa de Posgrado en Farmacología, Centro de Investigación y de Estudios Avanzados, Instituto Politécnico Nacional, A. P. 14-740, México D. F. 07000, Mexico
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