{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T14:08:55Z","timestamp":1769004535396,"version":"3.49.0"},"reference-count":19,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2009,1,28]],"date-time":"2009-01-28T00:00:00Z","timestamp":1233100800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ChemMedChem"],"published-print":{"date-parts":[[2009,3,16]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p><jats:bold>2\u2010Benzamidobenzoic acids<\/jats:bold> seem to stabilize PTPN22 phosphatase in its inactive 'open' conformation with the WPD loop locked in a distal position. In\u2005silico screening using both 3D structures in open and closed conformations yielded potent inhibitors of this potential drug target for autoimmunity that specifically dock into its open form. Tryptophan fluorescence measurements support the proposed binding mode.<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/gif\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/mcontent.gif\"><jats:alt-text>magnified image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p><jats:p>A gain\u2010of\u2010function mutant of the lymphoid phosphatase Lyp (PTPN22) has recently been implicated in type\u20051 diabetes and other autoimmune diseases, suggesting that small\u2010molecule inhibitors of Lyp could be useful for the treatment of autoimmunity. Virtual ligand screening (VLS) was applied in the search for hit compounds. Two different docking algorithms, FlexX and ICM, were used to screen a library of 'drug\u2010like' molecules against two different 3D structures, representing the catalytic site of Lyp in both the inactive 'open' and active 'closed' conformations. The top\u2010scoring compounds of each VLS run were tested for their inhibitory activity against recombinant Lyp. Interestingly, VLS with both active and inactive conformations yielded very potent hits, with IC<jats:sub>50<\/jats:sub> values in the sub\u2010 and low\u2010micromolar range. Moreover, many of these hits showed high docking scores only with one conformation. For instance, this was the case with several 2\u2010benzamidobenzoic acid derivatives, which specifically docked into the inactive open form. Tryptophan fluorescence measurements further support a binding mode in which these compounds seem to stabilize the phosphatase in its inactive conformation.<\/jats:p>","DOI":"10.1002\/cmdc.200800375","type":"journal-article","created":{"date-parts":[[2009,2,11]],"date-time":"2009-02-11T03:07:27Z","timestamp":1234321647000},"page":"440-444","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["In Silico Screening for PTPN22 Inhibitors: Active Hits from an Inactive Phosphatase Conformation"],"prefix":"10.1002","volume":"4","author":[{"given":"Shuangding","family":"Wu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Massimo","family":"Bottini","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert\u2005C.","family":"Rickert","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomas","family":"Mustelin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lutz","family":"Tautz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2009,3,11]]},"reference":[{"key":"e_1_2_6_1_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.77.3.1311"},{"key":"e_1_2_6_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2004.05.018"},{"key":"e_1_2_6_3_2","doi-asserted-by":"publisher","DOI":"10.1002\/ange.200461517"},{"key":"e_1_2_6_3_3","doi-asserted-by":"publisher","DOI":"10.1002\/anie.200461517"},{"key":"e_1_2_6_4_2","doi-asserted-by":"publisher","DOI":"10.1517\/14728222.10.1.157"},{"key":"e_1_2_6_5_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.26.021607.090418"},{"key":"e_1_2_6_6_2","doi-asserted-by":"crossref","first-page":"2013","DOI":"10.1182\/blood.V93.6.2013.406k25_2013_2024","volume":"93","author":"Cohen S.","year":"1999","journal-title":"Blood"},{"key":"e_1_2_6_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng1323"},{"key":"e_1_2_6_8_2","doi-asserted-by":"publisher","DOI":"10.1086\/422827"},{"key":"e_1_2_6_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.humimm.2004.09.016"},{"key":"e_1_2_6_10_2","doi-asserted-by":"publisher","DOI":"10.1086\/423790"},{"key":"e_1_2_6_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng1673"},{"key":"e_1_2_6_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymeth.2007.02.014"},{"key":"e_1_2_6_13_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.pharmtox.42.083001.144616"},{"key":"e_1_2_6_14_2","doi-asserted-by":"publisher","DOI":"10.1006\/jmbi.1996.0477"},{"key":"e_1_2_6_15_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-0134(1997)1 <215::AID-PROT29>3.0.CO;2-Q"},{"key":"e_1_2_6_16_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0706233104"},{"key":"e_1_2_6_17_2","doi-asserted-by":"publisher","DOI":"10.1021\/ci990423o"},{"key":"e_1_2_6_18_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bti770"}],"container-title":["ChemMedChem"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fcmdc.200800375","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cmdc.200800375","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T16:46:46Z","timestamp":1760287606000},"score":1,"resource":{"primary":{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/10.1002\/cmdc.200800375"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,3,11]]},"references-count":19,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2009,3,16]]}},"alternative-id":["10.1002\/cmdc.200800375"],"URL":"https:\/\/doi.org\/10.1002\/cmdc.200800375","archive":["Portico"],"relation":{},"ISSN":["1860-7179","1860-7187"],"issn-type":[{"value":"1860-7179","type":"print"},{"value":"1860-7187","type":"electronic"}],"subject":[],"published":{"date-parts":[[2009,3,11]]},"assertion":[{"value":"2008-11-11","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2009-03-11","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}