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Here, a native mass spectrometry approach was employed using pooled 100-compound mixtures, enabling the direct detection of intact HPPK\u2013ligand complexes in solution. Dual-mode MS acquisitions (low collision energy for complex detection and high collision energy for ligand confirmation), combined with an automated data analysis workflow, ensured robust identification of binding events from these complex samples. This strategy led to the identification of several HPPK-binding small molecules, all belonging to the dammarane triterpene glycoside (ginsenoside) class. Subsequent analysis of the hits revealed clear structure\u2013affinity relationships, highlighting how specific aglycone modifications and glycosylation patterns influence binding to HPPK. Our findings expand the known chemical space of HPPK ligands and demonstrate the utility of native MS-based screening coupled with automated data analysis to uncover new ligand scaffolds for challenging enzyme targets.<\/jats:p>","DOI":"10.3390\/molecules31122065","type":"journal-article","created":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T09:49:51Z","timestamp":1781257791000},"page":"2065","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Dual-Mode Native Mass Spectrometry Screening Identifies Ginsenoside Ligands of 6-Hydroxymethyl-7,8-Dihydropterin Pyrophosphokinase (HPPK)"],"prefix":"10.3390","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3160-4555","authenticated-orcid":false,"given":"Xinru","family":"Xue","sequence":"first","affiliation":[{"name":"Institute for Biomedicine and Glycomics, Griffith University, Southport, Gold Coast, QLD 4215, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4022-2623","authenticated-orcid":false,"given":"Ronald J.","family":"Quinn","sequence":"additional","affiliation":[{"name":"Institute for Biomedicine and Glycomics, Griffith University, Southport, Gold Coast, QLD 4215, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3908-8903","authenticated-orcid":false,"given":"Bernd H. A.","family":"Rehm","sequence":"additional","affiliation":[{"name":"Institute for Biomedicine and Glycomics, Griffith University, Southport, Gold Coast, QLD 4215, Australia"},{"name":"Centre for Cell Factories and Biopolymers, Institute for Biomedicine and Glycomics, Griffith University, Southport, Gold Coast, QLD 4215, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0056-0513","authenticated-orcid":false,"given":"Peter J.","family":"Myler","sequence":"additional","affiliation":[{"name":"Center for Global Infectious Disease Research, Seattle Children\u2019s Research Institute, Seattle, WA 98109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0930-3617","authenticated-orcid":false,"given":"Miaomiao","family":"Liu","sequence":"additional","affiliation":[{"name":"Institute for Biomedicine and Glycomics, Griffith University, Southport, Gold Coast, QLD 4215, Australia"},{"name":"School of Environment and Science, Griffith University, Nathan, Brisbane, QLD 4111, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Crombie, I.K. 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