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We have chosen thermolysin to validate our screening approach as it is a well\u2010studied enzyme and serves as a model system for other proteases. A protein\u2010targeted virtual library was designed and screening was carried out using the program AutoDock. Two fragment hits could be identified. For one of them, the crystal structure in complex with thermolysin is presented. This compound was selected for structure\u2010based optimization of binding affinity and improvement of ligand efficiency, while concomitantly keeping the fragment\u2010like properties of the initial hit. Redesigning the zinc coordination group revealed a novel class of fragments possessing<\/jats:italic> K<jats:italic><jats:sub>i<\/jats:sub> values as low as 128\u2005\u03bc<jats:sc>M<\/jats:sc>, thus they provide a good starting point for further hit evolution in a tailored lead design.<\/jats:italic><\/jats:p>","DOI":"10.1002\/cmdc.201000084","type":"journal-article","created":{"date-parts":[[2010,4,14]],"date-time":"2010-04-14T19:02:46Z","timestamp":1271271766000},"page":"930-940","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Fragment\u2010Based Lead Discovery: Screening and Optimizing Fragments for Thermolysin Inhibition"],"prefix":"10.1002","volume":"5","author":[{"given":"Lisa","family":"Englert","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katrin","family":"Silber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Holger","family":"Steuber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sascha","family":"Brass","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bj\u00f6rn","family":"Over","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans\u2010Dieter","family":"Gerber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Heine","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wibke\u2005E.","family":"Diederich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerhard","family":"Klebe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2010,5,31]]},"reference":[{"key":"e_1_2_6_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.drudis.2007.08.005"},{"key":"e_1_2_6_2_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm050850v"},{"key":"e_1_2_6_3_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm0305117"},{"key":"e_1_2_6_4_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm800382h"},{"key":"e_1_2_6_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2005.08.068"},{"key":"e_1_2_6_6_2","doi-asserted-by":"publisher","DOI":"10.1021\/cr030409h"},{"key":"e_1_2_6_7_2","doi-asserted-by":"publisher","DOI":"10.2174\/156802607782341073"},{"key":"e_1_2_6_8_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm0495778"},{"key":"e_1_2_6_9_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm8000289"},{"key":"e_1_2_6_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrd2220"},{"key":"e_1_2_6_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2005.11.038"},{"key":"e_1_2_6_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-894X(03)00237-3"},{"key":"e_1_2_6_13_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm050436v"},{"key":"e_1_2_6_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/0006-291X(69)90739-6"},{"key":"e_1_2_6_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/0003-9861(71)90331-6"},{"key":"e_1_2_6_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-291X(67)80122-0"},{"key":"e_1_2_6_17_2","doi-asserted-by":"publisher","DOI":"10.1021\/ar00153a003"},{"key":"e_1_2_6_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1359-6446(04)03069-7"},{"key":"e_1_2_6_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1359-6446(05)03511-7"},{"key":"e_1_2_6_20_2","doi-asserted-by":"publisher","DOI":"10.1021\/ci049714"},{"key":"e_1_2_6_21_2","doi-asserted-by":"publisher","DOI":"10.1021\/ci970429i"},{"key":"e_1_2_6_22_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-987X(19981115)19:14<1639::AID-JCC10>3.0.CO;2-B"},{"key":"e_1_2_6_23_2","doi-asserted-by":"publisher","DOI":"10.1006\/jmbi.1996.0477"},{"key":"e_1_2_6_24_2","doi-asserted-by":"publisher","DOI":"10.1006\/jmbi.1996.0897"},{"key":"e_1_2_6_25_2","doi-asserted-by":"publisher","DOI":"10.1002\/prot.10465"},{"key":"e_1_2_6_26_2","doi-asserted-by":"publisher","DOI":"10.1002\/prot.22058"},{"key":"e_1_2_6_27_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi050801k"},{"key":"e_1_2_6_28_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm0203783"},{"key":"e_1_2_6_29_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi00527a026"},{"key":"e_1_2_6_30_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi00319a010"},{"key":"e_1_2_6_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2009.04.051"},{"key":"e_1_2_6_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.drudis.2007.05.004"},{"key":"e_1_2_6_33_2","first-page":"471","volume":"4","author":"Olesen P. 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