TY  - JOUR
ID  - pittir17235
UR  - http://d-scholarship-dev.library.pitt.edu/17235/
IS  - 8
A1  - Jogalekar, AS
A1  - Damodaran, K
A1  - Kriel, FH
A1  - Jung, WH
A1  - Alcaraz, AA
A1  - Zhong, S
A1  - Curran, DP
A1  - Snyder, JP
Y1  - 2011/03/02/
N2  - 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/?-tubulin complex (Pose-2/Conf-2) that is gratifyingly compatible with the emerging DCT structure-activity data. © 2011 American Chemical Society.
JF  - Journal of the American Chemical Society
VL  - 133
SN  - 0002-7863
TI  - Dictyostatin flexibility bridges conformations in solution and in the ?-tubulin taxane binding site
SP  - 2427 
AV  - public
EP  -  2436
ER  -