1. Explain, for the non specialist, the significance of your article.

Paclitaxel (Taxol®) is a blockbuster drug; its name has become associated with the successful treatment of breast cancer. Discovered nearly four decades ago, Taxol has saved countless lives and grosses billions of dollars per year. In spite of its efficacy and high profile status, Taxol has proven nearly impossible to structurally characterize. It is relatively large and extremely flexible; there are many possible shapes (conformations) it might assume. Furthermore, it doesn't form crystals large enough to use in conventional single-crystal diffraction methods. Our laboratory has applied novel solid-state NMR (SSNMR) techniques to this challenging problem. Using experimental SSNMR data in concert with a computational grid search of conformation, we've matched experimental data of Taxol with a small number of highly likely structural conformations.

2. What has motivated you to conduct this work?

Dozens of people have tried, with limited success, to find the crystallographic structure of Taxol. We believed that SSNMR, with its sensitivity to conformation and hydrogen bonding, could provide insight into this molecule. After working on Taxol for several years, however, we realized that none of the standard NMR approaches were working. This was due to the size and flexibility of Taxol, and the presence of two geometrically distinct molecules in the solid. We therefore turned our attention to the development of new SSNMR and computational methods which have subsequently allowed us to gain access to a previously intractable problem.

3. Where do you see this work developing in the future?

Many pharmaceutical products suffer from the same difficulties that have plagued the study of Taxol. Polymorphism is extremely common among natural products. It has been said that "the number of forms known for a given compound is proportional to the time spent in research on that compound." Also common are amorphous and mixed phase compounds, dynamic molecules, and products which (like Taxol) have multiple molecules per asymmetric unit. It appears that our methods may alleviate some of these challenges. Additionally, since NMR may provide molecular shape, other studies such as x-ray structural analysis from powders can use this prior knowledge to simplify structural analysis.

4. Are there any particular challenges facing future research in this area?

Molecular size represents a major hurdle in this research. As molecular size increases, so does spectral complexity and the difficulty of a computational search of conformation space. Future work on large molecules will likely require selective labeling or other spectral simplifications in order to resolve individual NMR signals. Furthermore, our computational approach used a brute-force grid search method to ensure that the global minima was obtained. This type of grid-search would be undesirable on a larger molecule as it would likely kill the graduate student (or house-elf) who used it. While computational algorithms might be applied to assist in this search, comprehensive analysis of various algorithms has its own set of challenges.