Discodermolide conformation

The natural products eleutherobin (1), epothilone (23), paditaxel (24), nonataxel (25), and discodermolide (26) (Figure 6) show a similar mode of action. Furthermore, competitive inhibition of paditaxel binding to microtubules by epothilone, eleutherobin, and discodermolide is observed, and so a common pharmacophore and the existence of a common tubulin binding site are therefore strongly suggested [15]. The identification of comparable structural characteristics is complicated, since conformations established by NMR spectroscopy or X-ray structure analysis do not necessarily correspond to the binding conformations [16]-... 

The study of the tubulin-bound conformation of paclitaxel has resulted in a number of protein-ligand models, partially or fully based on the electron diffraction structure of aP-tubulin in paclitaxel-stabilized Zn2+-induced sheets [5, 12], Obviously, the nature of the paclitaxel binding site and the paclitaxel conformation in the binding site have key implications for the design of new MSA. A deep knowledge of the bioactive conformation would also help to explain how compounds as structurally diverse as the epothilones [48], discodermolide [49], and eleutherobin [50] have very similar mechanisms of action. 

Fig. 12 a Superimposition of the bound conformers of discodermolide and dictyostatin bound to assembled microtubules [94], b AUTODOCK solution of discodermolide and dictyostatin (blue) bound to tubulin (1JFF), also compared with bound paclitaxel (green)... 

Canales A, Matesanz R, Gardner NM, Andreu JM, Paterson I, Diaz JF, Jimenez-Barbero J (2008) The bound conformation of microtubule-stabilizing agents (II) NMR insights on the bioactive 3D structure of discodermolide and dictyostatin. Chemistry (DOI 10.1002/chem.200800039)... 

One of these methods is NAMFIS (NMR Analysis of Molecular Flexibility in Solution) [62], which considers all candidate conformations that are theoretically accessible to the molecule and optimizes their mole fractions until their computed variables match the experimental NMR data (usually NOEs and J couplings, in the future potentially also residual dipolar couplings). NAMFIS has been used to analyze the solution structures of several tubulin-binding drugs, such as PTX [63], epothilones [26], discodermolide [60] or laulimalide [64],... 

Fig- 17 The X-ray structure and three conformational classes of discodermolide identified by NAMFIS analysis of the NMR spectra in DMSO-d6. a The X-ray conformation, b The corkscrew form, c The sickle motif, d An extended or awl form. (Reprinted with permission from [60]. Copyright 2001 American Chemical Society)... 

Fig. 18 Stereoview of the overlaid tubulin-bound (NMR-derived, in gray [112]) and free (X-ray derived, in green [122]) conformations of discodermolide. Heteroatoms are displayed as spheres O in red and N in blue. The two conformations are quite similar except for the lactone moiety. (Reprinted with permission from [112]. Copyright 2006 Wiley-VCH Verlag GmbH Co. KGaA,...

Jogalekar, A.S., Kriel, F.H., Shi, Q Cornett, B Cicero, D and Snyder, J.P. (2010) The discodermolide hairpin structure flows conformationally stable modular motifs./. Med. Chem., 53,155-165. 

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