Field of Science

Constancy of the discodermolide hairpin motif
Our paper on the conformational analysis of discodermolide is now up on the ACS website. The following is a brief description of the work.

Discodermolide (DDM) is a well-known highly flexible polyketide that is the most potent microtubule polymerization agent known. In this capacity it functions very similar to taxol and the epothilones. However the binding mode of DDM will intimately depend on its conformations in solution.

To this end we have performed multiple force field conformational searches on DDM and the first surprising thing we noticed was that all four force fields located the same global minimum for the molecule in terms of geometry. This is surprising because, given the dissimilar parameterization criteria used in different force fields, minima obtained for flexible organic molecules are usually different for different force fields. Not only that, but all the minima closely superimposed on the x-ray structure of DDM which we call the "hairpin" motif. This is also surprising since the solid state structure of such a highly flexible molecule should not generally bear resemblance to a theoretically calculated global minimum.

Next, we used our NAMFIS methodology that combines parameters from conformational searches to coupling constants and interproton distances obtained from NMR data to determine DDM conformations in two solvents, water and DMSO. We were again surprised to see the x-ray/force field global minimum structure existing as a major component of the complex solution conformational ensemble. In many earlier studies, the x-ray structure has been located as a minor component so this too was unexpected.

However, this same structure has also been remarkably implicated as the bioactive conformation bound to tubulin by a series of elegant NMR experiments. To our knowledge, this is the first tubulin binder which has a single dominant preferred conformation in the solid-state, as a theoretical global minimum in multiple force field conformational searches, in solution as well as in the binding pocket of tubulin. In fact I personally don't know of any other molecule of this flexibility which exists as one dominant conformation in such extremely diverse environments; if this happened to every or even most molecules, drug discovery would suddenly become easier by an order of magnitude since all we would have to do to predict the binding mode of a drug would be to crystallize it or to look at its theoretical energy minima. To rationalize this very pronounced conformational preference of DDM, we analyze the energetics of three distributed synthons (methyl-hydroxy-methyl triads) in the molecule using molecular mechanics and quantum chemical methods; it seems that these three synthons modulate the conformational preferences of the molecule and essentially override other interactions with solvent, adjacent crystal entities, and amino acid elements in the protein.

Finally, we supplement this conformational analysis with a set of docking experiments which lead to a binding mode that is different from the earlier one postulated by NMR (as of now there is no x-ray structure of DDM bound to tubulin). We rationalize this binding mode in the light of SAR data for the molecule and describe why we prefer it to the previous one.

In summary then, DDM emerges as a unique molecule which seems to exist in one dominant conformation in highly dissimilar environments. The study also indicates the use of reinforcing synthons as modular elements to control conformation.

Jogalekar, A., Kriel, F., Shi, Q., Cornett, B., Cicero, D., & Snyder, J. (2009). The Discodermolide Hairpin Structure Flows from Conformationally Stable Modular Motifs Journal of Medicinal Chemistry DOI: 10.1021/jm9015284


  1. Ashutosh, please drop me an e-mail to my institute address

    I have a somewhat interesting second-hand information about an unpublished order-of-magnitude more potent Discodermolide-related natural compound (a closely-related macrocyclic analog) that seems to fit your NMR/modeling studies in the J Med Chem paper.

    Thanx, Milkshake

  2. The result is not surprising, and it doesn't take a force field or a computer to recognize the rigid nature of the molecule. Take a hard, conformation-analytical look at the middle (about C8 to C16) of discodermolide-- it is a textbook example of avoidance of syn-pentane interactions and A1,2 + A1,3 strain. The only major regions of flexibility in the molecule are regions flanking the middle (the delta-lactone region can spin a bit, and the diene has some rotational freedom). Add to that the distinct possibility of a hydrogen bond between the lactone hydroxyl and the carbamate nitrogen and, voila, rigid acyclic molecule.

  3. Ah, well, I did just read your J Med Chem ASAP manuscript, wherein you mention all but the A1,2 portion of my argument. My apologies for "dis'ing" you (sp.?) before reading. Nice paper, BTW. Also, kudos to the person who drew the figures (and knew the appropriate way to orient the hatched triangular bonds for the substituents in the alpha orientation). Structure 2 is the only one in the manuscript that contains the commonly found error in this regard.

  4. Anon: Thanks. You are indeed right about the A 1,2 and A 1,3 aspect. However the conformational behavior was still surprising because even with the avoidance of this strain you still expect a fair number of conformations in solution. Obviously the force fields are very good at modeling this strain, but we were more surprised to find a disproportionate percentage of the conformer in solution. In past studies we have found that even constraining elements nonetheless impart a fair degree of flexibility to such molecules.

    And thanks, the figures were drawn with Pymol.


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