SUMMARY
Researchers in the UCLA Department of physiology have invented a new drug discovery system based on high throughput screening.
BACKGROUND
Atomic resolution structures are critical to understanding how proteins and small molecule function, therefore being an important step in the drug discovery, development and delivery process. Traditionally, the structures of the protein-ligand interactions were investigated through macromolecular crystallography by soaking ligands into the protein crystal lattice or co-crystallizing the protein with the ligand. However, both the methods are suboptimal i.e., they either cause structural changes in the ligand or cause crystal soaked with the ligand to crack or dissolve, and in a worse case, making the crystal diffraction difficult.
To address the shortcomings of macromolecular crystallography, microcrystal electron diffraction (MicroED), an electron cryo-microscopy (cryoEM) method is alternatively used to study the atomic resolution structures for novel proteins and small drug molecules in a transmission electron microscope (TEM). This method utilizes co-crystallization of the protein and ligand prior to their application to the grid.
Given the benefits of MicroED in determining atomic structures of small drug molecules a new method of characterizing the protein-ligand structures has been described here, that has the potential of substantially expediting the future drug discovery and delivery process.
INNOVATION
UCLA researchers have developed a method for high throughput, on-grid soaking of ligands into protein microcrystals that is fast, simple, and effective. On-grid soaking of protein microcrystals is proved to effectively incorporate ligands. The researchers demonstrated that soaked microcrystals of the same protein-ligand complex have a better characterization result than using a much larger crystal required for X-ray scattering experiments.
POTENTIAL APPLICATIONS
- Protein structure study
- High throughput drug discovery
- Drug development by protein structure screening
- Applicable for other cryoEM modalities such as electron cryotomography
ADVANTAGES
- Fast and simple procedure
- Highly efficacious
- Better crystallography data than conventional method
- Easy access to data
- Easy and straightforward sample prep
- Lower investment of time and resources
DEVELOPMENT-TO-DATE
The prototype has been prepared and successfully demonstrated.