Fragment-based library generation for the discovery of a peptidomimetic p53-Mdm4 inhibitor
| Autor: | Yijun Huang, Katarzyna Guzik, Alexander Dömling, James A. Gaugler, Siglinde Wolf, Katarzyna Lesniak, Laurie K. Rijkee, Tad A. Holak, André Boltjes, Rob van de Velde |
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| Přispěvatelé: | Drug Design, Groningen Research Institute of Pharmacy, Medicinal Chemistry and Bioanalysis (MCB) |
| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Models
Molecular library generation Stereochemistry Peptidomimetic PROTEINS Protein Data Bank (RCSB PDB) Ligands 01 natural sciences Cocrystal Molecular Docking Simulation 03 medical and health sciences ANTAGONISTS Drug Discovery Humans Protein Interaction Maps 030304 developmental biology Indole test chemistry.chemical_classification LEAD COMPOUNDS 0303 health sciences P53 010405 organic chemistry Drug discovery Chemistry Ugi four-component reaction Proto-Oncogene Proteins c-mdm2 General Chemistry General Medicine Small molecule Combinatorial chemistry 0104 chemical sciences Amino acid peptidomimetic p53-Mdm4 inhibitor Peptidomimetics Tumor Suppressor Protein p53 MDMX Research Article |
| Zdroj: | Acs combinatorial science, 16(8), 393-396. AMER CHEMICAL SOC ACS Combinatorial Science |
| ISSN: | 2156-8952 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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