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While up to billions of compounds can be screened simultaneously in affinity\u2010based selections, the validation and characterization of individual hits discovered from DEL selections is a substantial bottleneck since it can be cumbersome and time\u2010consuming. Here, we describe the use of native mass spectrometry for the speedy hit validation of On\u2010DNA compounds. Through the preservation of noncovalent interactions in the gas phase, complexes of proteins and their respective On\u2010DNA ligands can be analyzed without further need of labeling or immobilization. By utilizing the workflow described in this work, we were able to reliably rank affinities of various purified On\u2010DNA binders or demonstrate binding of On\u2010DNA compounds from unpurified mixtures, mitigating the need for tedious purification steps. Additionally, the methodology described here can offer valuable insight on which moiety of a binding molecule contributes the most to binding, facilitating subsequent medicinal chemistry efforts for lead expansion.<\/jats:p>","DOI":"10.1002\/anie.202504470","type":"journal-article","created":{"date-parts":[[2025,6,12]],"date-time":"2025-06-12T10:48:53Z","timestamp":1749725333000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Native Mass Spectrometry Facilitates Hit Validation in DNA\u2010Encoded Library Technology"],"prefix":"10.1002","volume":"64","author":[{"given":"Philipp","family":"Bittner","sequence":"first","affiliation":[{"name":"Laboratory of Organic Chemistry Department of Chemistry and Applied Biosciences  ETH Zurich Zurich 8093 Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Gloger","sequence":"additional","affiliation":[{"name":"Institute of 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