Native Mass Spectrometry Facilitates Validation of DEL Hits

Hit validation is a crucial step in drug discovery based on DNA-encoded libraries (DEL). Rapid and accurate resynthesis of compounds, along with subsequent validation, can significantly accelerate the drug discovery process. The groups of Professors Jörg Scheuermann and Renato Zenobi from ETH Zurich developed a new method for validating on-DNA compounds with the support of the WuXi Biology DEL team, and published an article titled “Native Mass Spectrometry Facilitates Hit Validation in DNA-encoded Library Technology”.

Native mass spectrometry (MS) preserves non-covalent interactions in the gas phase, enabling the analysis of protein-ligand complexes without the need for labeling or immobilization. This paper describes the use of native MS for on-DNA hit validation in DEL technology. By utilizing the workflow described in this study, reliable Kd values of purified on-DNA compounds can be measured, and binding events of unpurified on-DNA compounds can be demonstrated using unlabeled, native-state proteins, providing valuable insights into protein-ligand interactions.

Combining WuXi Biology’s rapid and reliable on-DNA resynthesis capabilities, this method presents a promising new approach to expedite the hit validation process following DEL screening, while reducing the likelihood of false-negative results.