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A Focused DNA-Encoded Chemical Library for the Discovery of Inhibitors of NAD+-Dependent Enzymes
- Source :
- Journal of the American Chemical Society. 141:5169-5181
- Publication Year :
- 2019
- Publisher :
- American Chemical Society (ACS), 2019.
-
Abstract
- DNA-encoded chemical libraries are increasingly used in pharmaceutical research because they enable the rapid discovery of synthetic protein ligands. Here we explored whether target-class focused DNA-encoded chemical libraries can be cost-effective tools to achieve robust screening productivity for a series of proteins. The study revealed that a DNA-encoded library designed for NAD+-binding pockets (NADEL) effectively sampled the chemical binder space of enzymes with ADP-ribosyltransferase activity. The extracted information directed the synthesis of inhibitors for several enzymes including PARP15 and SIRT6. The high dissimilarity of NADEL screening fingerprints for different proteins translated into inhibitors that showed selectivity for their target. The discovery of patterns of enriched structures for six out of eight tested proteins is remarkable for a library of 58 302 DNA-tagged structures and illustrates the prospect of focused DNA-encoded libraries as economic alternatives to large library platforms.
- Subjects :
- chemistry.chemical_classification
Synthetic protein
Extramural
Drug discovery
DNA-encoded chemical library
Nad dependent
General Chemistry
Computational biology
010402 general chemistry
01 natural sciences
Biochemistry
Catalysis
0104 chemical sciences
Colloid and Surface Chemistry
Enzyme
chemistry
NAD+ kinase
Pharmaceutical sciences
Subjects
Details
- ISSN :
- 15205126 and 00027863
- Volume :
- 141
- Database :
- OpenAIRE
- Journal :
- Journal of the American Chemical Society
- Accession number :
- edsair.doi...........192ea47599bcf06dff2d16ad66b6569f