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Considerable effort is therefore devoted to developing low molecular weight inhibitors as starting points for antiviral drugs. Here, we present the results of an NMR screening study of PLPro for binding to the DSI\u2010poised fragment library containing 607 compounds. Based on saturation\u2010transfer difference (STD)\u2010 and WaterLOGSY\u2010NMR experiments, we identified 86 binding compounds. We prioritized five candidates for further in\u2010depth analysis. For three of those, we determined dissociation constants and two distinct binding sites on PLPro. These compounds could serve as a basis for future drug design studies in medicinal chemistry.<\/jats:p>","DOI":"10.1002\/2211-5463.70082","type":"journal-article","created":{"date-parts":[[2025,7,2]],"date-time":"2025-07-02T01:39:56Z","timestamp":1751420396000},"page":"1667-1677","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["<scp>NMR<\/scp> screening of low molecular weight inhibitors targeting the papain\u2010like protease (<scp>PLPro<\/scp>) of <scp>SARS<\/scp>\u2010<scp>CoV<\/scp>\u20102"],"prefix":"10.1002","volume":"15","author":[{"given":"Dennis J.","family":"Pyper","sequence":"first","affiliation":[{"name":"Institute of Organic Chemistry and Chemical Biology, Center for Biomolecular Magnetic Resonance (BMRZ) Goethe\u2010University Frankfurt\/M  Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sridhar","family":"Sreeramulu","sequence":"additional","affiliation":[{"name":"Institute of Organic Chemistry and Chemical Biology, Center for Biomolecular Magnetic Resonance (BMRZ) Goethe\u2010University Frankfurt\/M  Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benjamin T.","family":"Lanham","sequence":"additional","affiliation":[{"name":"Center for Biomolecular Structure and Organization, Department of Chemistry and Biochemistry University of Maryland  College Park MD USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elizabeth M.","family":"Engle","sequence":"additional","affiliation":[{"name":"Center for Biomolecular Structure and Organization, Department of Chemistry and Biochemistry University of Maryland  College Park MD USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Fushman","sequence":"additional","affiliation":[{"name":"Center for Biomolecular Structure and Organization, Department of Chemistry and Biochemistry University of Maryland  College Park MD USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5693-7909","authenticated-orcid":false,"given":"Harald","family":"Schwalbe","sequence":"additional","affiliation":[{"name":"Institute of Organic Chemistry and Chemical Biology, Center for Biomolecular Magnetic Resonance (BMRZ) Goethe\u2010University Frankfurt\/M  Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,7]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/d41586-022-00104-8"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41579-024-01036-y"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.REV120.013930"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/cbic.202200327"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41579-018-0020-5"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2601-5"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-21060-3"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2024.117909"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0510851103"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0805240105"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1039\/C5SC03115J"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmolb.2021.653148"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-38031-5"},{"key":"e_1_2_11_15_1","article-title":"Nmr\u2010based fragment screening in a minimum sample but maximum automation mode","volume":"2021","author":"Berg H","year":"2021","journal-title":"J Vis Exp"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202205858"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1006\/jmre.2000.2020"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10858-010-9461-5"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmr.2007.04.002"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10858-013-9715-0"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pnmrs.2013.02.001"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M309184200"},{"key":"e_1_2_11_23_1","first-page":"1","article-title":"The complex structure of GRL0617 and SARS\u2010CoV\u20102 PLpro reveals a hot spot for antiviral drug discovery. 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