TY - JOUR
T1 - Studies of (-)-pironetin binding to α-tubulin
T2 - Conformation, docking, and molecular dynamics
AU - Bañuelos-Hernández, Angel E.
AU - Mendoza-Espinoza, José Alberto
AU - Pereda-Miranda, Rogelio
AU - Cerda-García-Rojas, Carlos M.
PY - 2014/5/2
Y1 - 2014/5/2
N2 - 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 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.
AB - 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 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.
UR - http://www.scopus.com/inward/record.url?scp=84899869573&partnerID=8YFLogxK
U2 - 10.1021/jo500420j
DO - 10.1021/jo500420j
M3 - Artículo
C2 - 24761989
AN - SCOPUS:84899869573
SN - 0022-3263
VL - 79
SP - 3752
EP - 3764
JO - Journal of Organic Chemistry
JF - Journal of Organic Chemistry
IS - 9
ER -