A Focused DNA-Encoded Chemical Library for the Discovery of Inhibitors of NAD+-Dependent Enzymes.

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Yuen LH, Dana S, Liu Y, Bloom SI, Thorsell AG, Neri D, Donato AJ, Kireev D, Schüler H, Franzini RM

J. Am. Chem. Soc. 141 (13) 5169-5181 [2019-04-03; online 2019-03-19]

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.

Protein Science Facility (PSF) [Service]

PubMed 30855951

DOI 10.1021/jacs.8b08039

Crossref 10.1021/jacs.8b08039