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Fragment-based library generation for the discovery of a peptidomimetic p53-Mdm4 inhibitor
peptidomimetic p53-Mdm4 inhibitor
library generation
Ugi four-component reaction
On the basis of our recently resolved first cocrystal structure of Mdm4 in complex with a small molecule inhibitor (PDB ID 3LBJ), we devised an approach for the generation of potential Mdm4 selective ligands. We performed the Ugi four-component reaction (Ugi-4CR) in 96-well plates with an indole fragment, which is specially designed to mimic Trp23, a key amino acid for the interaction between p53 and Mdm4. Generally the reaction yielded mostly precipitates collected by 96-well filter plates. The best hit compound was found to be active and selective for Mdm4 (Ki = 5 μM, 10-fold stronger than Mdm2). This initial hit may serve as the starting point for designing selective p53-Mdm4 inhibitor with higher affinity.
dc.abstract.en | On the basis of our recently resolved first cocrystal structure of Mdm4 in complex with a small molecule inhibitor (PDB ID 3LBJ), we devised an approach for the generation of potential Mdm4 selective ligands. We performed the Ugi four-component reaction (Ugi-4CR) in 96-well plates with an indole fragment, which is specially designed to mimic Trp23, a key amino acid for the interaction between p53 and Mdm4. Generally the reaction yielded mostly precipitates collected by 96-well filter plates. The best hit compound was found to be active and selective for Mdm4 (Ki = 5 μM, 10-fold stronger than Mdm2). This initial hit may serve as the starting point for designing selective p53-Mdm4 inhibitor with higher affinity. | pl |
dc.affiliation | Wydział Chemii : Zakład Chemii Organicznej | pl |
dc.contributor.author | Boltjes, André | pl |
dc.contributor.author | Haung, Yijun | pl |
dc.contributor.author | Van De Velde, Rob | pl |
dc.contributor.author | Rijkee, Laurie | pl |
dc.contributor.author | Wolf, Siglinde | pl |
dc.contributor.author | Gaugler, James | pl |
dc.contributor.author | Kubica, Katarzyna - 154222 | pl |
dc.contributor.author | Guzik, Katarzyna - 151366 | pl |
dc.contributor.author | Holak, Tadeusz - 214380 | pl |
dc.contributor.author | Dömling, Alexander | pl |
dc.date.accessioned | 2015-06-23T10:00:54Z | |
dc.date.available | 2015-06-23T10:00:54Z | |
dc.date.issued | 2014 | pl |
dc.description.additional | Na publikacji autorka Kubica Katarzyna podpisana jako Leśniak Katarzyna. Na publikacji autor podpisany: Tad A. Holak. Katarzyna Guzik, Katarzyna Leśniak - Wydział Chemii UJ. | pl |
dc.description.number | 8 | pl |
dc.description.physical | 393-396 | pl |
dc.description.volume | 16 | pl |
dc.identifier.doi | 10.1021/co500026b | pl |
dc.identifier.eissn | 2156-8944 | pl |
dc.identifier.issn | 2156-8952 | pl |
dc.identifier.uri | http://ruj.uj.edu.pl/xmlui/handle/item/10089 | |
dc.language | eng | pl |
dc.language.container | eng | pl |
dc.rights.licence | bez licencji | |
dc.subject.en | peptidomimetic p53-Mdm4 inhibitor | pl |
dc.subject.en | library generation | pl |
dc.subject.en | Ugi four-component reaction | pl |
dc.subtype | Article | pl |
dc.title | Fragment-based library generation for the discovery of a peptidomimetic p53-Mdm4 inhibitor | pl |
dc.title.journal | ACS Combinatorial Science | pl |
dc.type | JournalArticle | pl |
dspace.entity.type | Publication |