Abstract
Theoretical conformational analysis of (-)-pironetin, a potent inhibitor of tubulin assembly, was based on DFT NMR coupling constants, showing two solvent-dependent conformational families. Docking studies of the pironetin-tubulin complex revealed hydrogen bond interactions with αAsn249, αAsn258 and αLys352 and supported formation of a covalent adduct between the αLys352 and the β carbon atom of pironetin lactone ring. Saturation transfer difference NMR spectroscopy confirmed that pironetin binds to tubulin, while molecular dynamics exposed a distortion of the M-loop between the αIle274 and αLeu285, an essential region for molecular recognition between α-α and β-β units of protofilaments.
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