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Functional assays reveal that sulfation enhances anticoagulant activity by \u223c5-fold, demonstrating that even rigid scaffolds can benefit from this modification. Modeling studies uncover a synergistic mechanism wherein the sulfate group engages in a hydrogen-bond network, electrostatic bridging, and charge-complementary interactions with thrombin exosite I, while the hydrophobic core (notably Phe106 and Val126) remains the primary driving force.<\/jats:p>","DOI":"10.1021\/acs.orglett.6c02797","type":"journal-article","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T05:05:46Z","timestamp":1785128746000},"page":"10057-10062","source":"Crossref","is-referenced-by-count":0,"title":["Site-Specific\nTyrosine Sulfation of Triabin via Semi-Synthesis\nEnhances Thrombin Inhibition through Synergistic Multiple-Mode Interactions"],"prefix":"10.1021","volume":"28","author":[{"given":"Zhenbang","family":"Xiao","sequence":"first","affiliation":[{"name":"South China University of Technology , , ,","place":["Guangzhou, China, 510640"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeyuan","family":"Mo","sequence":"additional","affiliation":[{"name":"South China University of Technology , , ,","place":["Guangzhou, China, 510640"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Litong","family":"Lin","sequence":"additional","affiliation":[{"name":"South China University of Technology , , ,","place":["Guangzhou, China, 510640"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4596-0032","authenticated-orcid":true,"given":"Chunmao","family":"He","sequence":"additional","affiliation":[{"name":"South China University of Technology , , ,","place":["Guangzhou, China, 510640"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,7,25]]},"reference":[{"issue":"9","key":"2026080709074322900_cit1","doi-asserted-by":"publisher","first-page":"933","DOI":"10.1515\/hsz-2012-0162","article-title":"Identification\nof Protease Exosite-Interacting Peptides that Enhance Substrate Cleavage\nKinetics","volume":"393","author":"Jabaiah","year":"2012","journal-title":"Biol. 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