New drug discovery is a critical step for improving patients' lives. First, researchers must identify molecules in the body's cells that help drive disease, as these are potential targets for new drugs. The next step is to screen candidate drugs that can hit those targets. However, screening can be a challenging and time-consuming process.
In a new study published in Nature Communications, a team at Osaka University has developed a technology that streamlines drug discovery using single-molecule tracking. This method allows the researchers to explore the effects of many different candidate drugs on a single target molecule. Building on the team's large-scale intracellular single molecule imaging system, referred to as AiSIS, the technology screens new drugs 100 times faster than standard manual techniques.
The team tested their new method to screen drugs that can target the epidermal growth factor receptor (EGFR), a molecule central to the development and progression of various cancers. Because several drugs that block EGFR are already available to treat lung cancer, this was a good way to determine how well their screening approach worked.
"We used a library of over 1,000 approved drugs to validate our screening method," says Daisuke Watanabe, lead author of the study. "We successfully identified all the drugs that are known to target EGFR and are currently used to treat cancer patients. More importantly, we found that the library included seven drugs that until now were not known to affect EGFR."
The new imaging technique visualizes the behavior of EGFR following treatment with each drug, allowing the researchers to examine how it reacted. For example, it is now possible to see changes in the assembly and disassembly of target molecules in response to drug treatment, a process known as multimer formation.
"Screening using single-molecule imaging provides a new means to discover drugs by observing the movement of biomolecules in cells and the formation of multimers," explains senior author Masahiro Ueda. "This has not been used for drug discovery until now, and it means we should be able to develop new drugs with different mechanisms of action and even repurpose already approved drugs to new targets."
Because this study demonstrated that the researchers' method worked as expected using the well-known EGFR target, they can now use this approach to screen drugs that could potentially hit an array of other receptor targets that are closely involved in disease development and progression.
Fig. 1
Top) Drug screening with automated system for in-cell single-molecule imaging. Bottom) Diffusion coefficient of the receptor (left) and cluster formation (right) were measured from 1,000 cells. These distributions obtained by every cell changed with EGF stimulation.
Credit: 2024 Ueda et al., Single molecule tracking based drug screening. Nature Communications
Fig. 2
Top) Library used for the screening. Color dots indicate the selected drugs. Bottom) 10 TKIs (left) and other 7 drugs (right) are included. MSD denotes mean square displacement of receptor diffusion.
Credit: 2024 Ueda et al., Single molecule tracking based drug screening. Nature Communications
Fig. 3
Three different mechanisms of action for drugs effective for EGFR which were selected by single-molecule tracking-based screening.
Credit: 2024 Ueda et al., Single molecule tracking based drug screening. Nature Communications
The article, "Single molecule tracking based drug screening," was published in Nature Communications at DOI: https://doi.org/10.1038/s41467-024-53432-w.
