Characterization of Specific N-α-Acetyltransferase 50 (Naa50) Inhibitors Identified Using a DNA Encoded Library
Autor: | Paul G. Richardson, Xiaoyun Meng, Karen A. Maegley, A.E. Stewart, Pei-Pei Kung, Jose L Montano, Ya-Li Deng, Jinqiao Wan, Michael R. Gehring, Jordan L. Meier, Brigitte S Naughton, Stephan Grant, Dou Dengfeng, Chakrapani Subramanyam, Anthony R. Harris, Samantha Elizabeth Greasley, Barry A. Morgan, Wen Yan, Xuemin Cheng, Prakash B. Palde, William K Sonnenburg, Junli Feng, Chen Qiuxia, Thomas A Paul, Gary M. Gallego, Sylvie K. Sakata, Sergei Timofeevski, Patrick Bingham, Benjamin J. Burke, Alex Shaginian |
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Rok vydání: | 2020 |
Předmět: |
chemistry.chemical_classification
010405 organic chemistry Chemistry Stereochemistry Organic Chemistry Target engagement Substrate (chemistry) 01 natural sciences Biochemistry Cocrystal 0104 chemical sciences 010404 medicinal & biomolecular chemistry Enzyme Mechanism of action Acetyltransferase Drug Discovery medicine A-DNA medicine.symptom Selectivity |
Zdroj: | ACS Med Chem Lett |
ISSN: | 1948-5875 |
Popis: | [Image: see text] Two novel compounds were identified as Naa50 binders/inhibitors using DNA-encoded technology screening. Biophysical and biochemical data as well as cocrystal structures were obtained for both compounds (3a and 4a) to understand their mechanism of action. These data were also used to rationalize the binding affinity differences observed between the two compounds and a MLGP peptide-containing substrate. Cellular target engagement experiments further confirm the Naa50 binding of 4a and demonstrate its selectivity toward related enzymes (Naa10 and Naa60). Additional analogs of inhibitor 4a were also evaluated to study the binding mode observed in the cocrystal structures. |
Databáze: | OpenAIRE |
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