Prioritizing multiple therapeutic targets in parallel using automated DNA-encoded library screening.

Area of Science:

• Medicinal Chemistry
• Drug Discovery
• Chemical Biology

Background:

• Identifying and prioritizing drug targets is crucial for new medicine discovery.
• Existing methods for target identification and prioritization can be time-consuming and resource-intensive.

Purpose of the Study:

• To develop and validate a novel method for rapid screening of multiple protein targets.
• To assess the utility of DNA-encoded library technology (ELT) for evaluating protein ligandability.
• To discover antibacterial leads and chemical series against challenging pathogens.

Main Methods:

• Utilized DNA-encoded library technology (ELT) for parallel screening of proteins.
• Screened 119 targets from Acinetobacter baumannii and Staphylococcus aureus.
• Screened 42 targets from Mycobacterium tuberculosis.

Main Results:

• Identified active chemical series for six targets from the initial screening.
• Discovered three chemotypes for DHFR from Mycobacterium tuberculosis.
• Demonstrated that parallel ELT selections can effectively assess protein ligandability.

Conclusions:

• Parallel ELT selections offer a rapid and efficient approach to assess protein ligandability.
• This method accelerates the discovery of potential drug leads and research tools.
• Highlights opportunities for developing new therapeutics against bacterial infections.