{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T06:43:57Z","timestamp":1792046637495,"version":"4.4.0"},"reference-count":63,"publisher":"Wiley","issue":"18","license":[{"start":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T00:00:00Z","timestamp":1790121600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T00:00:00Z","timestamp":1790121600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ChemBioChem"],"published-print":{"date-parts":[[2026,9,28]]},"abstract":"<jats:p>\n                    Artificial intelligence\u2010assisted virtual screening enables identification of chemically diverse bioactive small molecules. We targeted transglutaminase 2 (TG2), a multifunctional protein associated with mesenchymal\u2010like features in breast cancer. Approximately 10 million compounds were screened against the catalytic site of open TG2 using the AtomNet structure\u2010based deep\u2010learning model. The top 30,000 candidates underwent physicochemical and structural filtering, diversity clustering, and manual selection, yielding 84 compounds for experimental evaluation. Fourteen induced apoptosis in MCF\u20107, eight retained activity in MDA\u2010MB\u2010436, and three in MDA\u2010MB\u2010231 cells, also reducing transamidase activity in cellular lysates. Chemical\u2010space and fingerprint analyses placed\n                    <jats:bold>C10<\/jats:bold>\n                    ,\n                    <jats:bold>C12,<\/jats:bold>\n                    and\n                    <jats:bold>G11<\/jats:bold>\n                    outside the principal clusters of known active TG2 inhibitors, identifying structurally differentiated, nonpeptidic scaffolds. Docking into open and intermediate TG2 conformations consistently ranked\n                    <jats:bold>G11<\/jats:bold>\n                    as the most favorable candidate, with predicted binding near the catalytic core. In a 5\u2010(biotinamido)pentylamine (5\u2010BAP\u2010based assay,\n                    <jats:bold>G11<\/jats:bold>\n                    inhibited purified recombinant human TG2 with an IC\n                    <jats:sub>50<\/jats:sub>\n                    of 7.64\u2009\u00b1\u20092.87\u2009\u03bcM, while an independent dimethyl casein\u2013dansyl cadaverine assay confirmed concentration\u2010dependent inhibition and yielded an estimated\n                    <jats:italic>\n                      K\n                      <jats:sub>i<\/jats:sub>\n                    <\/jats:italic>\n                    of 44\u2009\u00b1\u200911\u2009\u03bcM, assuming competitive inhibition with respect to the substrate. Finally,\n                    <jats:bold>G11<\/jats:bold>\n                    did not significantly affect the viability of HEK293 cells, which express negligible or very low levels of TG2.\n                  <\/jats:p>","DOI":"10.1002\/cbic.70542","type":"journal-article","created":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T13:02:53Z","timestamp":1790168573000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Artificial Intelligence and Virtual Screening to Identify Small Molecules Inhibiting Transglutaminase 2 for Investigation and Treatment of Breast Cancer"],"prefix":"10.1002","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9430-8625","authenticated-orcid":false,"given":"Carlo M.","family":"Bergamini","sequence":"first","affiliation":[{"name":"Department of Neuroscience and Rehabilitation University of Ferrara  Ferrara Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7916-0757","authenticated-orcid":false,"given":"Niel M.","family":"Henriksen","sequence":"additional","affiliation":[{"name":"Atomwise Inc.  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