A specific and covalent JNK-1 ligand selected from an encoded self-assembling chemical library
| العنوان: | A specific and covalent JNK-1 ligand selected from an encoded self-assembling chemical library |
|---|---|
| المؤلفون: | Gunther Zimmermann, Stefan Knapp, Davor Bajic, Sara Vanetti, Ulrike Rieder, Jörg Scheuermann, Dario Neri, Martin Mattarella, Apirat Chaikuad |
| المصدر: | Chemistry-A European Journal Chemistry-A European Journal, 23 (34) |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | 0301 basic medicine, Ligands, 01 natural sciences, Catalysis, Article, Chemical library, Small Molecule Libraries, 03 medical and health sciences, Residue (chemistry), chemistry.chemical_compound, Moiety, Mitogen-Activated Protein Kinase 8, Binding site, Gene Library, biology, 010405 organic chemistry, Chemistry, Organic Chemistry, Active site, General Chemistry, Combinatorial chemistry, 3. Good health, 0104 chemical sciences, 030104 developmental biology, Covalent bond, biology.protein, Linker, Cysteine |
| الوصف: | We describe the construction of a DNA-encoded chemical library comprising 148’135 members, generated through the self-assembly of two sub-libraries, containing 265 and 559 members, respectively. The library was designed to contain building blocks potentially capable of forming covalent interactions with target proteins. Selections performed against JNK1, a kinase containing a conserved cysteine residue close to the ATP binding site, revealed the preferential enrichment of a 2-phenoxynicotinic acid moiety (building block A82) and a 4-(3,4-difluorophenyl)-4-oxobut-2-enoic acid moiety (building block B272). When the two compounds were joined by a short PEG linker, the resulting bidentate binder (A82-L-B272) was able to covalently modify JNK1 in the presence of a large molar excess of glutathione (0.5 mM), used to simulate intracellular reducing conditions. By contrast, derivatives of the individual building blocks were not able to covalently modify JNK1 in the same experimental conditions. The A82-L-B272 ligand was selective over related kinases (BTK and GAK), which also contain targetable cysteine residues in the vicinity of the active site. |
| وصف الملف: | application/application/pdf |
| اللغة: | English |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::9ea3d8140aaa8add5e929be92f0dab13 https://europepmc.org/articles/PMC5557334/ |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....9ea3d8140aaa8add5e929be92f0dab13 |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |