@article{pittir17235,
          volume = {133},
          number = {8},
           month = {March},
          author = {AS Jogalekar and K Damodaran and FH Kriel and WH Jung and AA Alcaraz and S Zhong and DP Curran and JP Snyder},
           title = {Dictyostatin flexibility bridges conformations in solution and in the {\ensuremath{\beta}}-tubulin taxane binding site},
         journal = {Journal of the American Chemical Society},
           pages = {2427 -- 2436},
            year = {2011},
             url = {http://d-scholarship-dev.library.pitt.edu/17235/},
        abstract = {Dictyostatin (DCT, 1) is a complex, flexible polyketide macrolide that demonstrates potent microtubule-polymerization activity. Both a solution structure (2a) and a possible binding mode for DCT (Conf-1) have been proposed by earlier NMR experiments. In the present study, the conformational landscape of DCT in DMSO-d6 and methanol-d4 was explored using extensive force-field-based conformational searches combined with geometric parameters derived from solution NMR data. The results portray a diversity of conformations for dictyostatin that illustrates the molecule's flexibility and excludes the previously suggested dominant solution conformation 2a. One conformation present in DMSO-d6 with a 7\% population (Conf-2, 0.6 kcal/mol above the global minimum at 298?) also satisfies the TR-NOESY NMR parameters of Canales et al. that characterize the taxane binding-site interaction between DCT and assembled microtubules in water. Application of several docking methods (Glide, Autodock, and RosettaLigand) has identified a low-energy binding model of the DCT/{\ensuremath{\beta}}-tubulin complex (Pose-2/Conf-2) that is gratifyingly compatible with the emerging DCT structure-activity data. {\copyright} 2011 American Chemical Society.}
}