Small Molecule Structure Determination

Knowledge of the 3D structures of drug molecules can inform all steps of drug discovery, from small molecule identification and characterization, optimization of synthesis, understanding structure-activity relationship (SAR), to formulations and drug delivery. Current approaches to structure determination are limited by the requirement of having large, well diffracting crystals (for x-ray diffraction), or low complexity (for NMR and mass spectroscopy).  Generation of large crystals for X-ray experiments is resource and time intensive, and not always feasible. Similarly, for highly complex systems, NMR and mass spectroscopy may provide only ambiguous results. 

  

In 2019, NIS developed a robust sample-to-structure workflow for microcrystal electron diffraction (microED) of small molecules (<1000Da): our pipeline provides data of excellent quality from which more than 20 previously unknown structures were determined in the first 6 months of development. We have since expanded on this early success to provide data acquisition-only services for more rapidly adopting groups. Learn about our access modes through our "Working With Us" resource. 


Related Applications:

  • Medicinal Chemistry: Atomic-resolution crystal structures elucidated by microED can be of great use at all stages of drug design and development. The minimal sample requirements, rapid turnaround time and ability to determine structures not possible/practical by other methods, make this an attractive additional to any medicinal chemist's arsenal.
  • Process Chemistry & Formulation: MicroED can identify undesired reaction products, inform mechanistic inquiries, direct synthetic chemistry strategies and be coupled with X-ray powder diffraction to rapidly screen for product purity. Crystal structures determined by microED can identify sites of proton transfer, distinguish between co-crystals and drug salts, confirm distinct polymorphs and, in some cases, elucidate chirality. These studies also return important information on lattice and crystal packing, which can be important for pharmacokinetics.
  • Natural Products & Metabolite Identification: Ongoing NIS developments in microED will include handling protocols for extremely limiting sample quantities to specifically support identification of intermediates formed by biosynthetic pathways and novel molecules isolated during metabolomics studies.  

  • Nannenga, B. L. (2020). MicroED methodology and development. Structural Dynamics, 7(1), 014304. https://doi.org/10.1063/1.5128226
  • Jones, C. G., Martynowycz, M. W., Hattne, J., Fulton, T. J., Stoltz, B. M., Rodriguez, J. A., Nelson, H. M., & Gonen, T. (2018). The CryoEM Method MicroED as a Powerful Tool for Small Molecule Structure Determination. ACS Central Science, 4(11), 1587–1592. https://doi.org/10.1021/acscentsci.8b00760
  • Kunde, T., & Schmidt, B. M. (2019). Microcrystal Electron Diffraction (MicroED) for Small‐Molecule Structure Determination. Angewandte Chemie International Edition, 58(3), 666–668. https://doi.org/10.1002/anie.201813215

Get to know our team

Speak with our experts about our chemistry services.

Contact Us