Native Mass Spectrometry Facilitates Hit Validation in DNA-Encoded Library Technology

Area of Science:

• Biochemistry
• Drug Discovery
• Analytical Chemistry

Background:

• DNA-encoded Library (DEL) technology is a powerful tool in drug development, enabling screening of billions of compounds.
• Validating and characterizing hits from DEL selections is a significant bottleneck due to time-consuming processes.

Purpose of the Study:

• To introduce native mass spectrometry as a method for rapid validation of On-DNA compounds from DEL screens.
• To streamline the hit identification and characterization process in DEL technology.

Main Methods:

• Utilizing native mass spectrometry to analyze noncovalent complexes of proteins and On-DNA ligands in the gas phase.
• Analyzing purified On-DNA binders and unpurified mixtures to assess binding and rank affinities.

Main Results:

• Successfully demonstrated the ability to rank affinities of purified On-DNA binders.
• Showcased the capability to detect binding of On-DNA compounds from unpurified mixtures, reducing purification needs.
• Provided insights into the binding contributions of different molecular moieties.

Conclusions:

• Native mass spectrometry offers a rapid and efficient method for hit validation in DEL technology.
• This approach accelerates medicinal chemistry efforts by simplifying hit characterization and providing early insights into structure-activity relationships.