Small Molecule Structure Determination

NIS Molecule
Scientific rendering of 3D protein structure, structural biology | Nano Imaging
NIS Protein Structure

Knowledge of the 3D structures of drug molecules can inform all steps of drug discovery, from small molecule identification, optimization of synthesis, understanding structure-activity relationship (SAR), to formulations and drug delivery. Nuclear magnetic resonance (NMR), mass spectroscopy (MS) and single crystal X-ray diffraction (scXRD) have long been the preferred methods for small molecule structure determination. However, these approaches are limited by structural ambiguities left by NMR and MS of complex molecules, and the challenges associated with growing large crystals for scXRD. Growing large, well-ordered crystals for scXRD is generally resource and time intensive, and it is not always possible to grow suitable crystals from every compound of interest, especially for anhydrous crystal forms. The cryo-EM method microcrystal electron diffraction (MicroED), also known as 3D Electron Diffraction (3D ED), provides an attractive alternative as it is able to determine structures from microcrystalline powders, eliminating the need for crystallization trials in many cases.

Industrial chemists require a routine analytical tool that succeeds where other techniques fall short. MicroED provides fast and reliable structural information with minimal sample preparation. 

  • Requires as little as 1 mg of material
  • Ability to examine mixtures and in some cases solve multiple crystal structures from a single sample
  • Establish if a crystal form is a salt or a cocrystal, and identify the site of proton transfer
  • Identify unknown synthetic products or contaminants

NIS helps routinely perform structural determination of small molecules

Imagine gaining a more thorough understanding of the structural characteristics of your small molecules. NanoImaging Services’ deployment of MicroED makes this possible. Our robust sample-to-structure workflow for small molecules (<1000 Da) provides high quality data from which we have solved over 50 structures. The largest compound we have determined a structure of was ~1000 Da and the largest crystal structure was composed of four copies of a ~730 Da molecule (Z’=4). Our highest resolution structure hit 0.8 Å, but most pharmaceutical samples fall in the 0.9-1.1 Å range.

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