{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T23:29:42Z","timestamp":1793230182900,"version":"4.5.0"},"reference-count":72,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,12,11]],"date-time":"2025-12-11T00:00:00Z","timestamp":1765411200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T00:00:00Z","timestamp":1767571200000},"content-version":"vor","delay-in-days":25,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100012041","name":"Versus Arthritis","doi-asserted-by":"publisher","award":["23137"],"award-info":[{"award-number":["23137"]}],"id":[{"id":"10.13039\/501100012041","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/X009203\/1"],"award-info":[{"award-number":["MR\/X009203\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009982","name":"The Humane Research Trust","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100009982","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100000289","name":"Cancer Research UK","doi-asserted-by":"crossref","award":["C52879\/A29144"],"award-info":[{"award-number":["C52879\/A29144"]}],"id":[{"id":"10.13039\/501100000289","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Breast Cancer Now","award":["2023.11PR1656"],"award-info":[{"award-number":["2023.11PR1656"]}]},{"DOI":"10.13039\/501100002653","name":"Yorkshire Cancer Research","doi-asserted-by":"publisher","award":["YCRSPF\\2024\\100093"],"award-info":[{"award-number":["YCRSPF\\2024\\100093"]}],"id":[{"id":"10.13039\/501100002653","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"crossref","award":["WT093134AIA"],"award-info":[{"award-number":["WT093134AIA"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100007514","name":"Universit\u00e0 di Pisa","doi-asserted-by":"publisher","award":["PRA_2022_19"],"award-info":[{"award-number":["PRA_2022_19"]}],"id":[{"id":"10.13039\/501100007514","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000274","name":"British Heart Foundation","doi-asserted-by":"publisher","award":["FS\/IBSRF\/20\/25032"],"award-info":[{"award-number":["FS\/IBSRF\/20\/25032"]}],"id":[{"id":"10.13039\/501100000274","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Pharmacological inhibition of the extracellular zinc metalloprotease A Disintegrin-like And Metalloprotease domain with Thrombospondin type I motifs 5 (ADAMTS5) has been proposed as a treatment for osteoarthritis (OA), a degenerative disease characterized by cartilage loss. More recently, ADAMTS5 has been implicated in ovarian cancer (OC), due to its essential role in promoting cell migration and association with poor prognosis. ADAMTS5 major substrates are the proteoglycans aggrecan and versican, which support the structural integrity of the cartilage and the tumor microenvironment. We have recently described a non-chelating arylsulfonamide glycoconjugate, compound\n                    <jats:bold>4b<\/jats:bold>\n                    , as a selective ADAMTS5 inhibitor, and shown its effectiveness in an OC 3D model. Here, we modified the structure of\n                    <jats:bold>4b<\/jats:bold>\n                    to improve its biological activity. We showed that, while\n                    <jats:bold>4b<\/jats:bold>\n                    induces cytotoxicity in several cell lines as well as in porcine and human cartilage explants, its derivative\n                    <jats:bold>2<\/jats:bold>\n                    was tolerated at high micromolar concentrations and effective in inhibiting aggrecan degradation in human\n                    <jats:italic>ex vivo<\/jats:italic>\n                    OA explants and reducing directional OC cell migration and pseudopod elongation.\n                    <jats:italic>In silico<\/jats:italic>\n                    analyses provided a rationale behind the different biological activities of the two compounds. These findings highlight the potential of non-chelating glycoconjugated arylsulfonamides to treat pathologies characterized by excessive ADAMTS5 activity.\n                  <\/jats:p>","DOI":"10.1038\/s41598-025-29549-3","type":"journal-article","created":{"date-parts":[[2025,12,11]],"date-time":"2025-12-11T19:04:55Z","timestamp":1765479895000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Design, synthesis and biological activity of glycoconjugated ADAMTS5 exosite inhibitors: applications in osteoarthritis and ovarian cancer models"],"prefix":"10.1038","volume":"16","author":[{"given":"Doretta","family":"Cuffaro","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Blagg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuhiro","family":"Yamamoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Pinzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachele","family":"Bacchetti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengnan","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Tew","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Campagnolo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felicia","family":"D\u2019Andrea","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enrico","family":"Crispino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulio","family":"Rastelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Armando","family":"Rossello","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Rainero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Nuti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salvatore","family":"Santamaria","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,11]]},"reference":[{"issue":"1\u20132","key":"29549_CR1","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1111\/iep.12344","volume":"101","author":"S Santamaria","year":"2020","unstructured":"Santamaria, S. ADAMTS-5: A difficult teenager turning 20. Int. J. Exp. Pathol. 101 (1\u20132), 4\u201320. https:\/\/doi.org\/10.1111\/iep.12344 (2020).","journal-title":"Int. J. Exp. Pathol."},{"issue":"1","key":"29549_CR2","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1016\/j.actbio.2011.08.011","volume":"8","author":"PL Chandran","year":"2012","unstructured":"Chandran, P. L. & Horkay, F. Aggrecan, an unusual polyelectrolyte: review of solution behavior and physiological implications. Acta Biomater. 8 (1), 3\u201312. https:\/\/doi.org\/10.1016\/j.actbio.2011.08.011 (2012).","journal-title":"Acta Biomater."},{"key":"29549_CR3","doi-asserted-by":"publisher","first-page":"701959","DOI":"10.3389\/fmolb.2021.701959","volume":"8","author":"KWJ Rose","year":"2021","unstructured":"Rose, K. W. J., Taye, N., Karoulias, S. Z. & Hubmacher, D. Regulation of ADAMTS proteases. Front. Mol. Biosci. 8, 701959. https:\/\/doi.org\/10.3389\/fmolb.2021.701959 (2021).","journal-title":"Front. Mol. Biosci."},{"issue":"12","key":"29549_CR4","doi-asserted-by":"publisher","first-page":"200333","DOI":"10.1098\/rsob.200333","volume":"10","author":"S Santamaria","year":"2020","unstructured":"Santamaria, S. & de Groot, R. ADAMTS proteases in cardiovascular physiology and disease. Open. Biol. 10 (12), 200333. https:\/\/doi.org\/10.1098\/rsob.200333 (2020).","journal-title":"Open. Biol."},{"issue":"9","key":"29549_CR5","doi-asserted-by":"publisher","first-page":"1207","DOI":"10.1002\/art.24021","volume":"59","author":"L Murphy","year":"2008","unstructured":"Murphy, L. et al. Lifetime risk of symptomatic knee osteoarthritis. Arthritis Rheum. 59 (9), 1207\u20131213. https:\/\/doi.org\/10.1002\/art.24021 (2008).","journal-title":"Arthritis Rheum."},{"key":"29549_CR6","unstructured":"Kaplan, W. et al. Priority Medicines for Europe and the World. 2013 Update pp.68\u201374 (World Health Organization in Collaboration with Utrecht University and Boston University, 2013)."},{"key":"29549_CR7","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1016\/j.mce.2018.11.001","volume":"480","author":"O Savvidou","year":"2019","unstructured":"Savvidou, O. et al. Glucocorticoid signaling and osteoarthritis. Mol. Cell. Endocrinol. 480, 153\u2013166. https:\/\/doi.org\/10.1016\/j.mce.2018.11.001 (2019).","journal-title":"Mol. Cell. Endocrinol."},{"issue":"11","key":"29549_CR8","doi-asserted-by":"publisher","first-page":"6706","DOI":"10.1074\/jbc.M708647200","volume":"283","author":"K Fushimi","year":"2008","unstructured":"Fushimi, K., Troeberg, L., Nakamura, H., Lim, N. H. & Nagase, H. Functional differences of the catalytic and non-catalytic domains in human ADAMTS-4 and ADAMTS-5 in aggrecanolytic activity. J. Biol. Chem. 283 (11), 6706\u20136716. https:\/\/doi.org\/10.1074\/jbc.M708647200 (2008).","journal-title":"J. Biol. Chem."},{"issue":"8","key":"29549_CR9","doi-asserted-by":"publisher","first-page":"2547","DOI":"10.1002\/art.20558","volume":"50","author":"SS Glasson","year":"2004","unstructured":"Glasson, S. S. et al. Characterization of and osteoarthritis susceptibility in ADAMTS-4-knockout mice. Arthritis Rheum. 50 (8), 2547\u20132558. https:\/\/doi.org\/10.1002\/art.20558 (2004).","journal-title":"Arthritis Rheum."},{"issue":"7033","key":"29549_CR10","doi-asserted-by":"publisher","first-page":"644","DOI":"10.1038\/nature03369","volume":"434","author":"SS Glasson","year":"2005","unstructured":"Glasson, S. S. et al. Deletion of active ADAMTS5 prevents cartilage degradation in a murine model of osteoarthritis. Nature 434 (7033), 644\u2013648. https:\/\/doi.org\/10.1038\/nature03369 (2005).","journal-title":"Nature"},{"issue":"7033","key":"29549_CR11","doi-asserted-by":"publisher","first-page":"648","DOI":"10.1038\/nature03417","volume":"434","author":"H Stanton","year":"2005","unstructured":"Stanton, H. et al. ADAMTS5 is the major aggrecanase in mouse cartilage in vivo and in vitro. Nature 434 (7033), 648\u2013652. https:\/\/doi.org\/10.1038\/nature03417 (2005).","journal-title":"Nature"},{"issue":"3","key":"29549_CR12","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1042\/BJ20150758","volume":"471","author":"S Santamaria","year":"2015","unstructured":"Santamaria, S. et al. Antibody-based exosite inhibitors of ADAMTS-5 (aggrecanase-2). Biochem. J. 471 (3), 391\u2013401. https:\/\/doi.org\/10.1042\/BJ20150758 (2015).","journal-title":"Biochem. J."},{"issue":"8","key":"29549_CR13","doi-asserted-by":"publisher","first-page":"1254","DOI":"10.1016\/j.joca.2015.02.778","volume":"23","author":"J Larkin","year":"2015","unstructured":"Larkin, J. et al. Translational development of an ADAMTS-5 antibody for osteoarthritis disease modification. Osteoarthr. Cartil. 23 (8), 1254\u20131266. https:\/\/doi.org\/10.1016\/j.joca.2015.02.778 (2015).","journal-title":"Osteoarthr. Cartil."},{"issue":"4","key":"29549_CR14","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1080\/19420862.2017.1304341","volume":"9","author":"S Santamaria","year":"2017","unstructured":"Santamaria, S. et al. Development of a monoclonal anti-ADAMTS-5 antibody that specifically blocks the interaction with LRP1. MAbs 9 (4), 595\u2013602. https:\/\/doi.org\/10.1080\/19420862.2017.1304341 (2017).","journal-title":"MAbs"},{"issue":"6","key":"29549_CR15","doi-asserted-by":"publisher","first-page":"1246","DOI":"10.1002\/art.40080","volume":"69","author":"K Yamamoto","year":"2017","unstructured":"Yamamoto, K. et al. Inhibition of shedding of low-density lipoprotein receptor-related protein 1 reverses cartilage matrix degradation in osteoarthritis. Arthritis Rheumatol. 69 (6), 1246\u20131256. https:\/\/doi.org\/10.1002\/art.40080 (2017).","journal-title":"Arthritis Rheumatol."},{"issue":"11","key":"29549_CR16","doi-asserted-by":"publisher","first-page":"1807","DOI":"10.1016\/j.joca.2013.08.015","volume":"21","author":"R Chiusaroli","year":"2013","unstructured":"Chiusaroli, R. et al. Targeting of ADAMTS5\u2019s ancillary domain with the Recombinant mAb CRB0017 ameliorates disease progression in a spontaneous murine model of osteoarthritis. Osteoarthr. Cartil. 21 (11), 1807\u20131810. https:\/\/doi.org\/10.1016\/j.joca.2013.08.015 (2013).","journal-title":"Osteoarthr. Cartil."},{"key":"29549_CR17","doi-asserted-by":"publisher","unstructured":"Yuan, S. et al. The protease ADAMTS5 controls ovarian cancer cell invasion, downstream of Rab25. FEBS J. 2025 Mar 31. (2025). https:\/\/doi.org\/10.1111\/febs.70080","DOI":"10.1111\/febs.70080"},{"issue":"7","key":"29549_CR18","doi-asserted-by":"publisher","first-page":"C444","DOI":"10.1152\/ajpcell.00188.2015","volume":"309","author":"TL Yeung","year":"2015","unstructured":"Yeung, T. L. et al. Cellular and molecular processes in ovarian cancer metastasis. A review in the theme: cell and molecular processes in cancer metastasis. Am. J. Physiol. Cell. Physiol. 309 (7), C444\u2013C456. https:\/\/doi.org\/10.1152\/ajpcell.00188.2015 (2015).","journal-title":"Am. J. Physiol. Cell. Physiol."},{"key":"29549_CR19","doi-asserted-by":"publisher","first-page":"500","DOI":"10.3389\/fimmu.2015.00500","volume":"6","author":"H Bougherara","year":"2015","unstructured":"Bougherara, H. et al. Real-Time imaging of resident T cells in human lung and ovarian carcinomas reveals how different tumor microenvironments control T lymphocyte migration. Front. Immunol. 6, 500. https:\/\/doi.org\/10.3389\/fimmu.2015.00500 (2015).","journal-title":"Front. Immunol."},{"issue":"10","key":"29549_CR20","doi-asserted-by":"publisher","first-page":"1560","DOI":"10.1038\/sj.bjc.6603766","volume":"96","author":"F Arslan","year":"2007","unstructured":"Arslan, F. et al. The role of versican isoforms V0\/V1 in glioma migration mediated by transforming growth factor-beta2. Br. J. Cancer. 96 (10), 1560\u20131568. https:\/\/doi.org\/10.1038\/sj.bjc.6603766 (2007).","journal-title":"Br. J. Cancer"},{"key":"29549_CR21","doi-asserted-by":"publisher","first-page":"e13","DOI":"10.1002\/pgr2.13","volume":"1","author":"H Watanabe","year":"2023","unstructured":"Watanabe, H. Versican and versikine: the dynamism of the extracellular matrix. Proteoglycan Res. 1, e13. https:\/\/doi.org\/10.1002\/pgr2.13 (2023).","journal-title":"Proteoglycan Res."},{"key":"29549_CR22","doi-asserted-by":"publisher","first-page":"100054","DOI":"10.1016\/j.mbplus.2020.100054","volume":"9","author":"S Redondo-Garc\u00eda","year":"2020","unstructured":"Redondo-Garc\u00eda, S., Peris-Torres, C., Caracuel-Peramos, R. & Rodr\u00edguez-Manzaneque, J. C. ADAMTS proteases and the tumor immune microenvironment: lessons from substrates and pathologies. Matrix Biol. Plus. 9, 100054. https:\/\/doi.org\/10.1016\/j.mbplus.2020.100054 (2020).","journal-title":"Matrix Biol. Plus"},{"issue":"2","key":"29549_CR23","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1385\/MB:24:2","volume":"24","author":"FX Gomis-R\u00fcth","year":"2003","unstructured":"Gomis-R\u00fcth, F. X. Structural aspects of the Metzincin clan of metalloendopeptidases. Mol. Biotechnol. 24 (2), 157\u2013202. https:\/\/doi.org\/10.1385\/MB:24:2 (2003).","journal-title":"Mol. Biotechnol."},{"key":"29549_CR24","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1002\/pmic.201600389","volume":"17","author":"S Amar","year":"2017","unstructured":"Amar, S., Minond, D. & Fields, G. B. Clinical implications of compounds designed to inhibit ECM-Modifying metalloproteinases. Proteomics 17, 23\u201324. https:\/\/doi.org\/10.1002\/pmic.201600389 (2017).","journal-title":"Proteomics"},{"issue":"8","key":"29549_CR25","doi-asserted-by":"publisher","first-page":"2839","DOI":"10.1021\/jm101609j","volume":"54","author":"M Shiozaki","year":"2011","unstructured":"Shiozaki, M. et al. Discovery of (1S,2R,3R)-2,3-dimethyl-2-phenyl-1-sulfamidocyclopropanecarboxylates: novel and highly selective aggrecanase inhibitors. J. Med. Chem. 54 (8), 2839\u20132863. https:\/\/doi.org\/10.1021\/jm101609j (2011).","journal-title":"J. Med. Chem."},{"issue":"6","key":"29549_CR26","doi-asserted-by":"publisher","first-page":"2937","DOI":"10.1021\/acs.jmedchem.0c02008","volume":"64","author":"F Brebion","year":"2021","unstructured":"Brebion, F. et al. Discovery of GLPG1972\/S201086, a Potent, Selective, and orally bioavailable ADAMTS-5 inhibitor for the treatment of osteoarthritis. J. Med. Chem. 64 (6), 2937\u20132952. https:\/\/doi.org\/10.1021\/acs.jmedchem.0c02008 (2021).","journal-title":"J. Med. Chem."},{"key":"29549_CR27","doi-asserted-by":"publisher","first-page":"7061","DOI":"10.1021\/jm300449x","volume":"55","author":"H Deng","year":"2012","unstructured":"Deng, H. et al. Discovery of highly potent and selective small molecule ADAMTS-5 inhibitors that inhibit human cartilage degradation via encoded library technology (ELT). J. Med. Chem. 55, 7061\u20137079. https:\/\/doi.org\/10.1021\/jm300449x (2012).","journal-title":"J. Med. Chem."},{"issue":"20","key":"29549_CR28","doi-asserted-by":"publisher","first-page":"13505","DOI":"10.1021\/acs.jmedchem.2c01177","volume":"65","author":"D Cuffaro","year":"2022","unstructured":"Cuffaro, D., Ciccone, L., Rossello, A., Nuti, E. & Santamaria, S. Targeting aggrecanases for osteoarthritis therapy: from zinc chelation to exosite Inhibition. J. Med. Chem. 65 (20), 13505\u201313532. https:\/\/doi.org\/10.1021\/acs.jmedchem.2c01177 (2022).","journal-title":"J. Med. Chem."},{"key":"29549_CR29","doi-asserted-by":"publisher","unstructured":"Santamaria, S. et al. Exosite inhibition of ADAMTS-5 by a glycoconjugated arylsulfonamide. Sci Rep. 2021 11(1):949. (2021). https:\/\/doi.org\/10.1038\/s41598-020-80294-1","DOI":"10.1038\/s41598-020-80294-1"},{"issue":"1","key":"29549_CR30","doi-asserted-by":"publisher","first-page":"10914","DOI":"10.1038\/s41598-019-47494-w","volume":"9","author":"S Santamaria","year":"2019","unstructured":"Santamaria, S. et al. Exosites in hypervariable loops of ADAMTS spacer domains control substrate recognition and proteolysis. Sci. Rep. 9 (1), 10914. https:\/\/doi.org\/10.1038\/s41598-019-47494-w (2019).","journal-title":"Sci. Rep."},{"key":"29549_CR31","doi-asserted-by":"publisher","first-page":"1759720X2210902","DOI":"10.1177\/1759720X221090297","volume":"14","author":"WM Oo","year":"2022","unstructured":"Oo, W. M. & Hunter, D. J. Repurposed and investigational disease-modifying drugs in osteoarthritis (DMOADs). Ther. Adv. Musculoskelet. Dis. 14, 1759720X221090297. https:\/\/doi.org\/10.1177\/1759720X221090297 (2022).","journal-title":"Ther. Adv. Musculoskelet. Dis."},{"issue":"25","key":"29549_CR32","doi-asserted-by":"publisher","first-page":"18294","DOI":"10.1074\/jbc.M701523200","volume":"282","author":"C Gendron","year":"2007","unstructured":"Gendron, C. et al. Proteolytic activities of human ADAMTS-5: comparative studies with ADAMTS-4. J. Biol. Chem. 282 (25), 18294\u201318306. https:\/\/doi.org\/10.1074\/jbc.M701523200 (2007).","journal-title":"J. Biol. Chem."},{"issue":"10","key":"29549_CR33","doi-asserted-by":"publisher","first-page":"3515","DOI":"10.1096\/fj.08-112680","volume":"22","author":"L Troeberg","year":"2008","unstructured":"Troeberg, L. et al. Calcium Pentosan polysulfate is a multifaceted exosite inhibitor of aggrecanases. FASEB J. 22 (10), 3515\u20133524. https:\/\/doi.org\/10.1096\/fj.08-112680 (2008).","journal-title":"FASEB J."},{"issue":"20","key":"29549_CR34","doi-asserted-by":"publisher","first-page":"1330","DOI":"10.1056\/NEJM199505183322003","volume":"332","author":"TE Warkentin","year":"1995","unstructured":"Warkentin, T. E. et al. Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N Engl. J. Med. 332 (20), 1330\u20131335. https:\/\/doi.org\/10.1056\/NEJM199505183322003 (1995).","journal-title":"N Engl. J. Med."},{"issue":"10","key":"29549_CR35","doi-asserted-by":"publisher","first-page":"4871","DOI":"10.1182\/blood-2007-10-120543","volume":"111","author":"MA Crowther","year":"2008","unstructured":"Crowther, M. A. & Warkentin, T. E. Bleeding risk and the management of bleeding complications in patients undergoing anticoagulant therapy: focus on new anticoagulant agents. Blood 111 (10), 4871\u20134879. https:\/\/doi.org\/10.1182\/blood-2007-10-120543 (2008).","journal-title":"Blood"},{"key":"29549_CR36","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1016\/j.bioorg.2016.08.002","volume":"68","author":"T Koyama","year":"2016","unstructured":"Koyama, T., Hatano, K. & Matsuoka, K. Synthetic assembly of novel avidin-biotin-GlcNAc (ABG) complex as an attractive bio-probe and its interaction with wheat germ agglutinin (WGA). Bioorg. Chem. 68, 219\u2013225. https:\/\/doi.org\/10.1016\/j.bioorg.2016.08.002 (2016).","journal-title":"Bioorg. Chem."},{"issue":"4","key":"29549_CR37","doi-asserted-by":"publisher","first-page":"738","DOI":"10.1039\/c9ob02476j","volume":"18","author":"JB McArthur","year":"2020","unstructured":"McArthur, J. B. et al. L. pneumophila CMP-5,7-di-N-acetyllegionaminic acid synthetase (LpCLS)-involved chemoenzymatic synthesis of Sialosides and analogues. Org. Biomol. Chem. 18 (4), 738\u2013744. https:\/\/doi.org\/10.1039\/c9ob02476j (2020).","journal-title":"Org. Biomol. Chem."},{"key":"29549_CR38","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1007\/978-1-0716-3589-6_8","volume":"2747","author":"AF Minns","year":"2024","unstructured":"Minns, A. F. & Santamaria, S. Determination of versikine levels by Enzyme-Linked immunosorbent assay (ELISA). Methods Mol. Biol. 2747, 83\u201393. https:\/\/doi.org\/10.1007\/978-1-0716-3589-6_8 (2024).","journal-title":"Methods Mol. Biol."},{"key":"29549_CR39","doi-asserted-by":"publisher","unstructured":"Santamaria, S. & Yamamoto, K. Analysis of Aggrecanase Activity Using Neoepitope Antibodies. Methods Mol Biol2043:125\u2013136. (2020). https:\/\/doi.org\/10.1007\/978-1-4939-9698-8_11","DOI":"10.1007\/978-1-4939-9698-8_11"},{"issue":"2","key":"29549_CR40","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1021\/jm970494j","volume":"41","author":"DE Levy","year":"1998","unstructured":"Levy, D. E. et al. Matrix metalloproteinase inhibitors: a structure-activity study. J. Med. Chem. 41 (2), 199\u2013223. https:\/\/doi.org\/10.1021\/jm970494j (1998).","journal-title":"J. Med. Chem."},{"key":"29549_CR41","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1016\/j.neuro.2022.07.008","volume":"92","author":"L Lopez-Suarez","year":"2022","unstructured":"Lopez-Suarez, L., Awabdh, S. A., Coumoul, X. & Chauvet, C. The SH-SY5Y human neuroblastoma cell line, a relevant in vitro cell model for investigating neurotoxicology in human: focus on organic pollutants. NeuroToxicology 92, 131\u2013155. https:\/\/doi.org\/10.1016\/j.neuro.2022.07.008 (2022).","journal-title":"NeuroToxicology"},{"key":"29549_CR42","doi-asserted-by":"publisher","first-page":"105109","DOI":"10.1016\/j.tiv.2021.105109","volume":"73","author":"W Qu","year":"2021","unstructured":"Qu, W. et al. Exploration of xenobiotic metabolism within cell lines used for Tox21 chemical screening. Toxicol. Vitro. 73, 105109. https:\/\/doi.org\/10.1016\/j.tiv.2021.105109 (2021).","journal-title":"Toxicol. Vitro"},{"issue":"14\u201315","key":"29549_CR43","doi-asserted-by":"publisher","first-page":"2785","DOI":"10.1016\/s0045-6535(98)00321-x","volume":"37","author":"C Urani","year":"1998","unstructured":"Urani, C., Doldi, M., Crippa, S. & Camatini, M. Human-derived cell lines to study xenobiotic metabolism. Chemosphere 37 (14\u201315), 2785\u20132795. https:\/\/doi.org\/10.1016\/s0045-6535(98)00321-x (1998).","journal-title":"Chemosphere"},{"issue":"5","key":"29549_CR44","doi-asserted-by":"publisher","first-page":"742","DOI":"10.1021\/ci100050t","volume":"50","author":"D Rogers","year":"2010","unstructured":"Rogers, D. & Hahn, M. Extended-connectivity fingerprints. J. Chem. Inf. Model. 50 (5), 742\u2013754. https:\/\/doi.org\/10.1021\/ci100050t (2010).","journal-title":"J. Chem. Inf. Model."},{"issue":"6","key":"29549_CR45","doi-asserted-by":"publisher","first-page":"1273","DOI":"10.1021\/ci010132r","volume":"42","author":"JL Durant","year":"2002","unstructured":"Durant, J. L., Leland, B. A., Henry, D. R. & Nourse, J. G. Reoptimization of MDL keys for use in drug discovery. J. Chem. Inf. Comput. Sci. 42 (6), 1273\u20131280. https:\/\/doi.org\/10.1021\/ci010132r (2002).","journal-title":"J. Chem. Inf. Comput. Sci."},{"key":"29549_CR46","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1021\/ci00054a008","volume":"27","author":"R Nilakantan","year":"1987","unstructured":"Nilakantan, R., Bauman, N., Dixon, J. S. & Venkataraghavan, R. Topological torsion: a new molecular descriptor for SAR applications. Comparison with other descriptors. J. Chem. Inf. Comput. Sci. 27, 82\u201385. https:\/\/doi.org\/10.1021\/ci00054a008 (1987).","journal-title":"J. Chem. Inf. Comput. Sci."},{"key":"29549_CR47","doi-asserted-by":"publisher","first-page":"372","DOI":"10.1021\/acs.jcim.9b00821","volume":"60","author":"L Pinzi","year":"2020","unstructured":"Pinzi, L. & Rastelli, G. Identification of target associations for polypharmacology from analysis of crystallographic ligands of the protein data bank. J. Chem. Inf. Model. 60, 372\u2013390. https:\/\/doi.org\/10.1021\/acs.jcim.9b00821 (2020).","journal-title":"J. Chem. Inf. Model."},{"key":"29549_CR48","doi-asserted-by":"publisher","first-page":"E2567","DOI":"10.3390\/molecules24142567","volume":"24","author":"L Pinzi","year":"2019","unstructured":"Pinzi, L., Lherbet, C., Baltas, M., Pellati, F. & Rastelli, G. In Silico repositioning of Cannabigerol as a novel inhibitor of the Enoyl acyl carrier protein (ACP) reductase (InhA), mol. Basel Switz. 24, E2567. https:\/\/doi.org\/10.3390\/molecules24142567 (2019).","journal-title":"Basel Switz."},{"issue":"1\u20133","key":"29549_CR49","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1016\/s0169-409x(00)00129-0","volume":"46","author":"CA Lipinski","year":"2001","unstructured":"Lipinski, C. A., Lombardo, F., Dominy, B. W. & Feeney, P. J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv Rev. 46 (1\u20133), 3\u201326. https:\/\/doi.org\/10.1016\/s0169-409x(00)00129-0 (2001).","journal-title":"Adv. Drug Deliv Rev."},{"key":"29549_CR50","doi-asserted-by":"publisher","first-page":"106774","DOI":"10.1016\/j.phrs.2023.106774","volume":"191","author":"R Roskoski Jr","year":"2023","unstructured":"Roskoski, R. Jr. Rule of five violations among the FDA-approved small molecule protein kinase inhibitors. Pharmacol. Res. 191, 106774. https:\/\/doi.org\/10.1016\/j.phrs.2023.106774 (2023).","journal-title":"Pharmacol. Res."},{"key":"29549_CR51","doi-asserted-by":"publisher","first-page":"1759","DOI":"10.1016\/j.bmcl.2006.12.061","volume":"17","author":"MJ Waring","year":"2007","unstructured":"Waring, M. J. & Johnstone, C. A quantitative assessment of hERG liability as a function of lipophilicity. Bioorg. Med. Chem. Lett. 17, 1759\u20131764. https:\/\/doi.org\/10.1016\/j.bmcl.2006.12.061 (2007).","journal-title":"Bioorg. Med. Chem. Lett."},{"issue":"1","key":"29549_CR52","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1110\/ps.073287008","volume":"17","author":"L Mosyak","year":"2008","unstructured":"Mosyak, L. et al. Crystal structures of the two major Aggrecan degrading enzymes, ADAMTS4 and ADAMTS5. Protein Sci. 17 (1), 16\u201321. https:\/\/doi.org\/10.1110\/ps.073287008 (2008).","journal-title":"Protein Sci."},{"issue":"2","key":"29549_CR53","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1007\/BF00210790","volume":"14","author":"S Wojtowicz-Praga","year":"1996","unstructured":"Wojtowicz-Praga, S. et al. Phase I trial of a novel matrix metalloproteinase inhibitor Batimastat (BB-94) in patients with advanced cancer. Invest. New. Drugs. 14 (2), 193\u2013202. https:\/\/doi.org\/10.1007\/BF00210790 (1996).","journal-title":"Invest. New. Drugs"},{"key":"29549_CR54","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1111\/j.1747-0285.2009.00780.x","volume":"73","author":"G Rastelli","year":"2009","unstructured":"Rastelli, G., Degliesposti, G., Del Rio, A. & Sgobba, M. Binding Estimation after refinement, a new automated procedure for the refinement and rescoring of docked ligands in virtual screening. Chem. Biol. Drug Des. 73, 283\u2013286. https:\/\/doi.org\/10.1111\/j.1747-0285.2009.00780.x (2009).","journal-title":"Chem. Biol. Drug Des."},{"key":"29549_CR55","doi-asserted-by":"publisher","first-page":"636989","DOI":"10.3389\/fphar.2021.636989","volume":"12","author":"L Pinzi","year":"2021","unstructured":"Pinzi, L., Tinivella, A., Caporuscio, F. & Rastelli, G. Drug repurposing and polypharmacology to fight SARS-CoV-2 through Inhibition of the main protease. Front. Pharmacol. 12, 636989. https:\/\/doi.org\/10.3389\/fphar.2021.636989 (2021).","journal-title":"Front. Pharmacol."},{"key":"29549_CR56","doi-asserted-by":"publisher","first-page":"498","DOI":"10.3389\/fchem.2019.00498","volume":"7","author":"G Rastelli","year":"2019","unstructured":"Rastelli, G. & Pinzi, L. Refinement and rescoring of virtual screening results. Front. Chem. 7, 498. https:\/\/doi.org\/10.3389\/fchem.2019.00498 (2019).","journal-title":"Front. Chem."},{"issue":"12","key":"29549_CR57","doi-asserted-by":"publisher","first-page":"889","DOI":"10.1021\/ar000033j","volume":"33","author":"PA Kollman","year":"2000","unstructured":"Kollman, P. A. et al. Calculating structures and free energies of complex molecules: combining molecular mechanics and continuum models. Acc. Chem. Res. 33 (12), 889\u2013897. https:\/\/doi.org\/10.1021\/ar000033j (2000).","journal-title":"Acc. Chem. Res."},{"key":"29549_CR58","unstructured":"Schr\u00f6dinger Release 2024-2: LigPrep, Schr\u00f6dinger, LLC, New York, NY, (2024)."},{"issue":"D1","key":"29549_CR59","doi-asserted-by":"publisher","first-page":"D945","DOI":"10.1093\/nar\/gkw1074","volume":"45","author":"A Gaulton","year":"2017","unstructured":"Gaulton, A. et al. The chembl database in 2017. Nucleic Acids Res. 45 (D1), D945\u2013D954. https:\/\/doi.org\/10.1093\/nar\/gkw1074 (2017).","journal-title":"Nucleic Acids Res."},{"key":"29549_CR60","unstructured":"Schr\u00f6dinger Release 2024-2: QikProp, Schr\u00f6dinger, LLC, New York, NY, (2024)."},{"key":"29549_CR61","doi-asserted-by":"publisher","unstructured":"Jasial, S., Hu, Y., Vogt, M. & Bajorath, J. Activity-relevant similarity values for fingerprints and implications for similarity searching. F1000Research 5 (591). https:\/\/doi.org\/10.12688\/f1000research.8357.2 (2016).","DOI":"10.12688\/f1000research.8357.2"},{"key":"29549_CR62","unstructured":"Thresholds accessed on March 31st, for random in fingerprints the RDKit supports, (2025). https:\/\/greglandrum.github.io\/rdkit-blog\/posts\/2021-05-18-fingerprint-thresholds1.html, 2021."},{"key":"29549_CR63","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1007\/978-3-540-78246-9_38","volume-title":"Data Anal. Mach. Learn. Appl","author":"MR Berthold","year":"2008","unstructured":"Berthold, M. R. et al. KNIME: the Konstanz information miner, in: (eds Preisach, C., Burkhardt, H., Schmidt-Thieme, L. & Decker, R.) Data Anal. Mach. Learn. Appl., Springer, Berlin, Heidelberg, : 319\u2013326. doi: https:\/\/doi.org\/10.1007\/978-3-540-78246-9_38. (2008)."},{"key":"29549_CR64","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1007\/s10822-013-9644-8","volume":"27","author":"G Madhavi Sastry","year":"2013","unstructured":"Madhavi Sastry, G., Adzhigirey, M., Day, T., Annabhimoju, R. & Sherman, W. Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments. J. Comput. Aided Mol. Des. 27, 221\u2013234. https:\/\/doi.org\/10.1007\/s10822-013-9644-8 (2013).","journal-title":"J. Comput. Aided Mol. Des."},{"issue":"7","key":"29549_CR65","doi-asserted-by":"publisher","first-page":"1739","DOI":"10.1021\/jm0306430","volume":"47","author":"RA Friesner","year":"2004","unstructured":"Friesner, R. A. et al. Glide: a new approach for rapid, accurate Docking and scoring. 1. Method and assessment of Docking accuracy. J. Med. Chem. 47 (7), 1739\u20131749. https:\/\/doi.org\/10.1021\/jm0306430 (2004).","journal-title":"J. Med. Chem."},{"key":"29549_CR66","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1016\/0076-6879(95)48008-0","volume":"248","author":"CG Knight","year":"1995","unstructured":"Knight, C. G. Active-site Titration of peptidases. Methods Enzymol. 248, 85\u2013101. https:\/\/doi.org\/10.1016\/0076-6879(95)48008-0 (1995).","journal-title":"Methods Enzymol."},{"issue":"40","key":"29549_CR67","doi-asserted-by":"publisher","first-page":"27859","DOI":"10.1074\/jbc.M114.573287","volume":"289","author":"SJ Foulcer","year":"2014","unstructured":"Foulcer, S. J. et al. Determinants of versican-V1 proteoglycan processing by the metalloproteinase ADAMTS5. J. Biol. Chem. 289 (40), 27859\u201327873. https:\/\/doi.org\/10.1074\/jbc.M114.573287 (2014).","journal-title":"J. Biol. Chem."},{"key":"29549_CR68","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1016\/s0945-053x(02)00069-0","volume":"21","author":"MD Tortorella","year":"2002","unstructured":"Tortorella, M. D., Liu, R. Q., Burn, T., Newton, R. C. & Arner, E. Characterization of human aggrecanase 2 (ADAM-TS5): substrate specificity studies and comparison with aggrecanase 1 (ADAM-TS4). Matrix Biol. 21, 499\u2013511. https:\/\/doi.org\/10.1016\/s0945-053x(02)00069-0 (2002).","journal-title":"Matrix Biol."},{"key":"29549_CR69","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1016\/j.matbio.2024.12.005","volume":"135","author":"R de Groot","year":"2025","unstructured":"de Groot, R. et al. Cleavage of cartilage oligomeric matrix protein (COMP) by ADAMTS4 generates a neoepitope associated with osteoarthritis and other forms of degenerative joint disease. Matrix Biol. 135, 106\u2013124. https:\/\/doi.org\/10.1016\/j.matbio.2024.12.005 (2025).","journal-title":"Matrix Biol."},{"key":"29549_CR70","doi-asserted-by":"publisher","first-page":"511","DOI":"10.1096\/fj.12-216671","volume":"27","author":"K Yamamoto","year":"2013","unstructured":"Yamamoto, K. et al. LRP-1-mediated endocytosis regulates extracellular activity of ADAMTS-5 in articular cartilage. FASEB J. 27, 511\u2013521. https:\/\/doi.org\/10.1096\/fj.12-216671 (2013).","journal-title":"FASEB J."},{"key":"29549_CR71","doi-asserted-by":"publisher","first-page":"1251","DOI":"10.1038\/nm1125","volume":"10","author":"KW Cheng","year":"2004","unstructured":"Cheng, K. W. et al. The RAB25 small GTPase determines aggressiveness of ovarian and breast cancers. Nat. Med. 10, 1251\u20131256. https:\/\/doi.org\/10.1038\/nm1125 (2004).","journal-title":"Nat. Med."},{"issue":"5547","key":"29549_CR72","doi-asserted-by":"publisher","first-page":"1708","DOI":"10.1126\/science.1064829","volume":"294","author":"E Cukierman","year":"2001","unstructured":"Cukierman, E., Pankov, R., Stevens, D. R. & Yamada, K. M. Taking cell-matrix adhesions to the third dimension. Science 294 (5547), 1708\u20131712. https:\/\/doi.org\/10.1126\/science.1064829 (2001).","journal-title":"Science"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-29549-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-29549-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-29549-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T14:03:35Z","timestamp":1767621815000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-29549-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,11]]},"references-count":72,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["29549"],"URL":"https:\/\/doi.org\/10.1038\/s41598-025-29549-3","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,11]]},"assertion":[{"value":"29 September 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 November 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 December 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"329"}}