The Discodermolide Hairpin Structure Flows from Conformationally Stable Modular Motifs

Abstract

(+)-Discodermolide (DDM), a polyketide macrolide from marine sponge, is a potent microtubule assembly promoter. Reported solid-state, solution, and protein-bound DDM conformations reveal the unusual result that a common hairpin conformational motif exists in all three microenvironments. No other flexible microtubule binding agent exhibits such constancy of conformation. In the present study, we combine force-field conformational searches with NMR deconvolution in different solvents to compare DDM conformers with those observed in other environments. While several conformational families are perceived, the hairpin form dominates. The stability of this motif is dictated primarily by steric factors arising from repeated modular segments in DDM composed of the C(Me)-CHX-C(Me) fragment. Furthermore, docking protocols were utilized to probe the DDM binding mode in beta-tubulin. A previously suggested pose is substantiated (Pose-1), while an alternative (Pose-2) has been identified. SAR analysis for DDM analogues differentiates the two poses and suggests that Pose-2 is better able to accommodate the biodata.

The Lithistida: important sources of compounds useful in biomedical research

“…This set back, along with the observation of synergistic activity with paclitaxel has contributed to a significant interest in preparing analogs of discodermolide with reduced toxicity [34]. Substantial research has also gone into defining the binding pose of discodermolide bound to purified tubulin and assembled microtubules [35-37]. The majority of these use molecular mechanics calculations and NMR methods to define structural features in discodermolide that interact with tubulin and to rationalize these with the known structure activity data [34].…”

Conformations of stevastelin C3 analogs: Computational deconvolution of NMR data reveals conformational heterogeneity and novel motifs

“…Although NMR data in water has not been recorded, past studies have indicated that changes in solvent only entail a change in the distribution of already existing conformations without altering their essential form. 21,22 Such an identity-preserving shift in the populations of stevastelin conformers induced by other solvents would not be unanticipated. Relevant NMR data on stevastelins in water could make such an analysis computationally tractable.…”

“…Thus, NAMFIS serves as a useful alternative to purely theoretical methods for investigating molecular conformations. Previously, NAMFIS has been successfully used to determine bioactive conformations in solution for medicinally important molecules such as taxol, 19 epothilones, 20 discodermolide, 21 laulimalide, 22 and geldanamycin 23 and has also been used in the study of helical peptides. 24 In some of these studies, the bioactive conformation has been located as a relatively minor component of the solution ensemble amounting to not more than a few percent, underscoring the difficulty in teasing out these minor conformations from time-averaged structural data.…”

Design, synthesis and biological evaluation of a simplified fluorescently labeled discodermolide as a molecular probe to study the binding of discodermolide to tubulin

“…Docking studies then identified two distinct docking poses, and one of them was identified as better accommodating the available SAR data. 11 …”