2. Academic Validation
  3. MicroED as a powerful tool for structure determination of macrocyclic drug compounds directly from their powder formulations

MicroED as a powerful tool for structure determination of macrocyclic drug compounds directly from their powder formulations

  • bioRxiv. 2023 Aug 1:2023.07.31.551405. doi: 10.1101/2023.07.31.551405.
E Danelius 1 2,  G Bu 2,  H Wieske 3,  T Gonen 1 2 4
Affiliations

Affiliations

  • 1 Howard Hughes Medical Institute, University of California Los Angeles, Los Angeles, CA 90095, USA.
  • 2 Department of Biological Chemistry, University of California Los Angeles, 615 Charles E.Young Drive South, Los Angeles, CA 90095, USA.
  • 3 Department of Chemistry - BMC, Uppsala University, Husargatan 3, 75237 Uppsala, Sweden.
  • 4 Department of Physiology, University of California Los Angeles, 615 Charles E. Young Drive South, Los Angeles, CA 90095, USA.
PMID: 37577574 DOI: 10.1101/2023.07.31.551405
Abstract

Macrocycles are important drug leads with many advantages including the ability to target flat and featureless binding sites as well as act as molecular chameleons and thereby reach intracellular targets. However, due to their complex structures and inherent flexibility, macrocycles are difficult to study structurally and there are limited structural data available. Herein, we use the cryo-EM method MicroED to determine the novel atomic structures of several macrocycles which have previously resisted structural determination. We show that structures of similar complexity can now be obtained rapidly from nanograms of material, and that different conformations of flexible compounds can be derived from the same experiment. These results will have impact on contemporary drug discovery as well as natural product exploration.

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