Studies of (鈭?-Pironetin Binding to 伪-Tubulin: Conformation, Docking, and Molecular Dynamics
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- 作者：Angel E. Ba帽uelos-Hern谩ndez ; Jos茅 Alberto Mendoza-Espinoza ; Rogelio Pereda-Miranda ; Carlos M. Cerda-Garc铆a-Rojas
- 刊名：Journal of Organic Chemistry
- 出版年：2014
- 出版时间：May 2, 2014
- 年：2014
- 卷：79
- 期：9
- 页码：3752-3764
- 全文大小：692K
- 年卷期：v.79,no.9(May 2, 2014)
- ISSN：1520-6904
文摘
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鈥?sup>1H coupling constants comparison. Two solvent-dependent conformational families (L and M) were revealed for the optimum conformations. Docking studies of the pironetin鈥搕ubulin complex determined a quantitative model for the hydrogen-bond interactions of pironetin through the 伪Asn249, 伪Asn258, and 伪Lys352 amino groups in 伪-tubulin, which supported the formation of a covalent adduct between the 伪Lys352 and the 尾 carbon atom of the 伪,尾-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 伪-helices as well as at the S9 尾-sheet, where 伪Lys352 is located. A large structural perturbation in the M-loop geometry between the 伪Ile274 and 伪Leu285 residues, an essential region for molecular recognition between 伪鈥撐?and 尾鈥撐?units of protofilaments, was also identified and provided a rationale for the pironetin inhibitory activity.