{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T03:19:32Z","timestamp":1771816772446,"version":"3.50.1"},"reference-count":32,"publisher":"International Union of Crystallography (IUCr)","issue":"12","license":[{"start":{"date-parts":[[2014,11,22]],"date-time":"2014-11-22T00:00:00Z","timestamp":1416614400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/journals.iucr.org\/services\/copyrightpolicy.html"},{"start":{"date-parts":[[2014,11,22]],"date-time":"2014-11-22T00:00:00Z","timestamp":1416614400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/journals.iucr.org\/services\/copyrightpolicy.html#TDM"}],"content-domain":{"domain":["iucr.org","wiley.com","iucrj.org"],"crossmark-restriction":true},"short-container-title":["Acta Crystallogr D Biol Crystallogr","Acta Crystallogr D","Acta Crystallogr D Biol Cryst","Acta Cryst D","Acta Cryst D Biol Crystallogr","Acta Cryst D Biol Cryst","Acta Cryst Sect D","Acta Cryst Sect D Biol Cryst","Acta Crystallogr Sect D","Acta Crystallogr Sect D Biol Crystallogr"],"published-print":{"date-parts":[[2014,12,1]]},"abstract":"<jats:p>The aspartate pathway is essential for the production of the amino acids required for protein synthesis and of the metabolites needed in bacterial development. This pathway also leads to the production of several classes of quorum-sensing molecules that can trigger virulence in certain microorganisms. The second enzyme in this pathway, aspartate \u03b2-semialdehyde dehydrogenase (ASADH), is absolutely required for bacterial survival and has been targeted for the design of selective inhibitors. Fragment-library screening has identified a new set of inhibitors that, while they do not resemble the substrates for this reaction, have been shown to bind at the active site of ASADH. Structure-guided development of these lead compounds has produced moderate inhibitors of the target enzyme, with some selectivity observed between the Gram-negative and Gram-positive orthologs of ASADH. However, many of these inhibitor analogs and derivatives have not yet achieved the expected enhanced affinity. Structural characterization of these enzyme\u2013inhibitor complexes has provided detailed explanations for the barriers that interfere with optimal binding. Despite binding in the same active-site region, significant changes are observed in the orientation of these bound inhibitors that are caused by relatively modest structural alterations. Taken together, these studies present a cautionary tale for issues that can arise in the systematic approach to the modification of lead compounds that are being used to develop potent inhibitors.<\/jats:p>","DOI":"10.1107\/s1399004714023979","type":"journal-article","created":{"date-parts":[[2014,11,21]],"date-time":"2014-11-21T19:29:15Z","timestamp":1416598155000},"page":"3244-3252","update-policy":"https:\/\/doi.org\/10.1107\/cm_01","source":"Crossref","is-referenced-by-count":9,"title":["A cautionary tale of structure-guided inhibitor development against an essential enzyme in the aspartate-biosynthetic pathway"],"prefix":"10.1107","volume":"70","author":[{"given":"Alexander G.","family":"Pavlovsky","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bharani","family":"Thangavelu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pravin","family":"Bhansali","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ronald E.","family":"Viola","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"329","published-online":{"date-parts":[[2014,11,22]]},"reference":[{"key":"dw5116_bb1","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1107\/S0907444909052834","volume":"66","author":"Arachea","year":"2010","journal-title":"Acta Cryst. D"},{"key":"dw5116_bb2","doi-asserted-by":"crossref","first-page":"7374","DOI":"10.1021\/ja501354q","volume":"136","author":"Barelier","year":"2014","journal-title":"J. Am. Chem. Soc."},{"key":"dw5116_bb3","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1111\/j.1432-1033.1980.tb04399.x","volume":"104","author":"Biellmann","year":"1980","journal-title":"Eur. J. Biochem."},{"key":"dw5116_bb4","doi-asserted-by":"crossref","first-page":"1388","DOI":"10.1107\/S0907444904012971","volume":"60","author":"Blanco","year":"2004","journal-title":"Acta Cryst. D"},{"key":"dw5116_bb5","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1110\/ps.0230803","volume":"12","author":"Blanco","year":"2003","journal-title":"Protein Sci."},{"key":"dw5116_bb6","doi-asserted-by":"crossref","first-page":"12613","DOI":"10.1073\/pnas.1634958100","volume":"100","author":"Blanco","year":"2003","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"dw5116_bb7","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1038\/415545a","volume":"415","author":"Chen","year":"2002","journal-title":"Nature (London)"},{"key":"dw5116_bb8","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/B978-0-12-152801-0.50013-4","volume":"1","author":"Cohen","year":"1969","journal-title":"Curr. Top. Cell. Regul."},{"key":"dw5116_bb9","doi-asserted-by":"crossref","first-page":"2255","DOI":"10.1002\/cbic.200500172","volume":"6","author":"Cox","year":"2005","journal-title":"Chembiochem"},{"key":"dw5116_bb10","unstructured":""},{"key":"dw5116_bb11","doi-asserted-by":"crossref","first-page":"3463","DOI":"10.1021\/jm040031v","volume":"47","author":"Erlanson","year":"2004","journal-title":"J. Med. Chem."},{"key":"dw5116_bb12","doi-asserted-by":"crossref","first-page":"31031","DOI":"10.1074\/jbc.M605926200","volume":"281","author":"Faehnle","year":"2006","journal-title":"J. Biol. Chem."},{"key":"dw5116_bb13","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1016\/j.jmb.2005.09.027","volume":"353","author":"Faehnle","year":"2005","journal-title":"J. Mol. Biol."},{"key":"dw5116_bb14","doi-asserted-by":"crossref","first-page":"1042","DOI":"10.1177\/1087057110381383","volume":"15","author":"Gao","year":"2010","journal-title":"J. Biomol. Screen."},{"key":"dw5116_bb15","doi-asserted-by":"crossref","first-page":"5673","DOI":"10.1128\/JB.185.19.5673-5684.2003","volume":"185","author":"Gerdes","year":"2003","journal-title":"J. Bacteriol."},{"key":"dw5116_bb16","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1006\/jmbi.1999.2828","volume":"289","author":"Hadfield","year":"1999","journal-title":"J. Mol. Biol."},{"key":"dw5116_bb17","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1016\/S1359-6446(04)03069-7","volume":"9","author":"Hopkins","year":"2004","journal-title":"Drug Discov. Today"},{"key":"dw5116_bb18","doi-asserted-by":"crossref","first-page":"1346","DOI":"10.1021\/jm050850v","volume":"49","author":"Howard","year":"2006","journal-title":"J. Med. Chem."},{"key":"dw5116_bb19","doi-asserted-by":"crossref","first-page":"4678","DOI":"10.1073\/pnas.0730515100","volume":"100","author":"Kobayashi","year":"2003","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"dw5116_bb20","doi-asserted-by":"crossref","first-page":"2950","DOI":"10.1016\/j.bmc.2012.03.013","volume":"20","author":"Luniwal","year":"2012","journal-title":"Bioorg. Med. Chem."},{"key":"dw5116_bb21","doi-asserted-by":"crossref","first-page":"1389","DOI":"10.1016\/j.peptides.2003.11.026","volume":"25","author":"Lyon","year":"2004","journal-title":"Peptides"},{"key":"dw5116_bb22","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1038\/nsb0194-55","volume":"1","author":"Mattos","year":"1994","journal-title":"Nature Struct. Biol."},{"key":"dw5116_bb23","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1006\/prep.2002.1626","volume":"25","author":"Moore","year":"2002","journal-title":"Protein Expr. Purif."},{"key":"dw5116_bb24","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1107\/S0907444911001314","volume":"67","author":"Murshudov","year":"2011","journal-title":"Acta Cryst. D"},{"key":"dw5116_bb25","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/S0076-6879(97)76066-X","volume":"276","author":"Otwinowski","year":"1997","journal-title":"Methods Enzymol."},{"key":"dw5116_bb26","doi-asserted-by":"crossref","first-page":"6394","DOI":"10.1021\/bi00019a019","volume":"34","author":"Ouyang","year":"1995","journal-title":"Biochemistry"},{"key":"dw5116_bb27","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1111\/j.1747-0285.2011.01267.x","volume":"79","author":"Pavlovsky","year":"2012","journal-title":"Chem. Biol. Drug Des."},{"key":"dw5116_bb28","doi-asserted-by":"crossref","first-page":"2315","DOI":"10.1128\/JB.185.7.2315-2329.2003","volume":"185","author":"Ragkousi","year":"2003","journal-title":"J. Bacteriol."},{"key":"dw5116_bb29","doi-asserted-by":"crossref","first-page":"2293","DOI":"10.1021\/jm070091b","volume":"50","author":"Saxty","year":"2007","journal-title":"J. Med. Chem."},{"key":"dw5116_bb30","doi-asserted-by":"crossref","first-page":"4990","DOI":"10.1021\/bi3005126","volume":"51","author":"Scott","year":"2012","journal-title":"Biochemistry"},{"key":"dw5116_bb31","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1039\/a804532a","volume":"18","author":"Van Heijenoort","year":"2001","journal-title":"Nat. Prod. Rep."},{"key":"dw5116_bb32","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1021\/ar000057q","volume":"34","author":"Viola","year":"2001","journal-title":"Acc. Chem. Res."}],"container-title":["Acta Crystallographica Section D Biological Crystallography"],"original-title":[],"link":[{"URL":"http:\/\/journals.iucr.org\/d\/issues\/2014\/12\/00\/dw5116\/dw5116.pdf","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/journals.iucr.org\/d\/issues\/2014\/12\/00\/dw5116\/dw5116.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,1,13]],"date-time":"2025-01-13T10:01:55Z","timestamp":1736762515000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.iucr.org\/paper?S1399004714023979"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,11,22]]},"references-count":32,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2014,12]]}},"alternative-id":["S1399004714023979"],"URL":"https:\/\/doi.org\/10.1107\/s1399004714023979","relation":{},"ISSN":["1399-0047"],"issn-type":[{"value":"1399-0047","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,11,22]]},"assertion":[{"value":"Acta Crystallographica Section D: Biological Crystallography","name":"journal","label":"Publication","explanation":{"URL":"http:\/\/journals.iucr.org\/d"}},{"value":"research papers","name":"content_type","label":"Content type","explanation":{"URL":"http:\/\/journals.iucr.org\/d\/services\/notesforauthors.html"}},{"value":"Yes","order":0,"name":"peer_reviewed","label":"Peer reviewed","group":{"name":"peer_review","label":"Peer review"}},{"value":"Single blind","order":1,"name":"review_process","label":"Review process","group":{"name":"peer_review","label":"Peer review"}},{"value":"2 September 2014","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication history"}},{"value":"30 October 2014","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication history"}},{"value":"22 November 2014","order":2,"name":"published_online","label":"Published online","group":{"name":"publication_history","label":"Publication history"}},{"value":"This article has supporting information","name":"supplementary_materials","label":"Supplementary materials","explanation":{"URL":"http:\/\/scripts.iucr.org\/cgi-bin\/sendsup?dw5116"}},{"value":"\u00a9 2014 International Union of Crystallography","order":0,"name":"copyright","label":"Copyright","explanation":{"URL":"http:\/\/journals.iucr.org\/services\/copyrightpolicy.html"},"group":{"name":"copyright_and_licensing","label":"Copyright and licencing"}}]}}