Carnegie Mellon University
February 08, 2019

‘Gamechanger’ in Natural Product Structure Determination Published in Nature Protocols

By Ben Panko

A "gamechanger" set of methods published in the journal Nature Protocols by a team, including Carnegie Mellon Professor Roberto R. Gil, comprises work using nuclear magnetic resonance (NMR) spectroscopy on how to unambiguously determine the three-dimensional structure of molecules, such as natural or synthetic products that might not be crystallized for X-ray diffraction structure determination.

"Twenty years ago, this was science fiction," Gil said regarding the application of the technology to the analysis of small molecules, known as anisotropic NMR, which he and the other authors on the article have been working on for the last fifteen years.

"The work constitutes a major advance in the determination of the structure of small molecules that are isolated from nature," said co-author Christian Griesinger, director of the Max Planck Institute for Biophysical Chemistry in Göttingen, Germany.

NMR spectroscopy uses radio waves and intense magnetic fields to determine the molecular structure of compounds. However, when it comes to complex flexible organic small molecules, the data obtained from conventional NMR analysis, in which interatomic distances and so-called dihedral angles are measured, can often make it difficult or impossible to pin down the exact structure of the compounds due to the incompleteness of the data and the variety of the three-dimensional arrangement of the atoms making up the compound.

To overcome this problem, Gil and others have worked to develop gels that swell in different organic solvents into which samples can be placed. When compressed or stretched, these gels help align the molecules relative to the axis of the magnetic field, providing additional structural parameters derived from the orientation of interatomic bonds and functional moieties within the molecule.

In addition to these gel alignment media, the paper also tackles how to best acquire the NMR data and include them in the structure determination process. In particular, the article highlights computer software written by one of the corresponding authors Armando Navarro-Vázquez, a Professor at the Universidade Federal de Pernambuco (Recife, Brazil), which would allow scientists to convert the NMR data with a "push of a button" to get the structure of the molecule being studied.

"Anisotropic NMR has evolved into an extremely powerful technology thanks to years of methodology development from many research groups. With the Protocol article it can now be more easily accessed by small-molecule labs, working on natural products and converting them into drugs," said the other corresponding author Yizhou Liu, a research chemist at Merck (now Pfizer). He worked on the paper as part of a team at the pharmaceutical company Merck, together with his colleagues Thomas Williamson and Gary Martin. “Every pharmaceutical company-based NMR laboratory should pick it up,” states Yizhou Liu in the end.

"The paper strives to "demystify" the utilization of anisotropic NMR data, specifically RCSAs that were once thought to be largely inaccessible experimentally, moving this technique from the realm of the specialist NMR laboratory to put it in the hands of NMR-competent non-specialist investigators," state Gary Martin and Thomas Williamson jointly.

Gil agrees: "The main goal of this paper was to make this technology easily accessible to the community. We want people to be able to do it by themselves."