A Focused DNA-Encoded Chemical Library for the Discovery of Inhibitors of NAD+-Dependent Enzymes
Yuen, Lik Hang ; Dana, Srikanta ; Liu, Yu ; Bloom, Samuel I ; Thorsell, Ann-Gerd ; Neri, Dario ; Donato, Anthony J ; Kireev, Dmitri ; Schüler, Herwig LU
and Franzini, Raphael M
(2019)
In Journal of the American Chemical Society
141(13).
p.5169-5181
- 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... (More)
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.
(Less)
- author
- Yuen, Lik Hang
; Dana, Srikanta
; Liu, Yu
; Bloom, Samuel I
; Thorsell, Ann-Gerd
; Neri, Dario
; Donato, Anthony J
; Kireev, Dmitri
; Schüler, Herwig
LU
and Franzini, Raphael M
- publishing date
- 2019-04-03
- type
- Contribution to journal
- publication status
- published
- keywords
- ADP Ribose Transferases/antagonists & inhibitors, DNA/chemistry, Drug Discovery, Enzyme Inhibitors/chemistry, Humans, Models, Molecular, Molecular Structure, Sirtuins/antagonists & inhibitors, Small Molecule Libraries/chemistry
- in
- Journal of the American Chemical Society
- volume
- 141
- issue
- 13
- pages
- 13 pages
- publisher
- The American Chemical Society (ACS)
- external identifiers
-
- pmid:30855951
- scopus:85063410418
- ISSN
- 1520-5126
- DOI
- 10.1021/jacs.8b08039
- language
- English
- LU publication?
- no
- id
- ed0782d6-3af9-48b8-b8e6-8e25d766bd16
- date added to LUP
- 2024-11-21 17:46:54
- date last changed
- 2025-06-07 08:51:56
@article{ed0782d6-3af9-48b8-b8e6-8e25d766bd16,
abstract = {{<p>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.</p>}},
author = {{Yuen, Lik Hang and Dana, Srikanta and Liu, Yu and Bloom, Samuel I and Thorsell, Ann-Gerd and Neri, Dario and Donato, Anthony J and Kireev, Dmitri and Schüler, Herwig and Franzini, Raphael M}},
issn = {{1520-5126}},
keywords = {{ADP Ribose Transferases/antagonists & inhibitors; DNA/chemistry; Drug Discovery; Enzyme Inhibitors/chemistry; Humans; Models, Molecular; Molecular Structure; Sirtuins/antagonists & inhibitors; Small Molecule Libraries/chemistry}},
language = {{eng}},
month = {{04}},
number = {{13}},
pages = {{5169--5181}},
publisher = {{The American Chemical Society (ACS)}},
series = {{Journal of the American Chemical Society}},
title = {{A Focused DNA-Encoded Chemical Library for the Discovery of Inhibitors of NAD<sup>+</sup>-Dependent Enzymes}},
url = {{http://dx.doi.org/10.1021/jacs.8b08039}},
doi = {{10.1021/jacs.8b08039}},
volume = {{141}},
year = {{2019}},
}