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Identification of structure-activity relationships from screening a structurally compact DNA-encoded chemical library

Franzini, Raphael M ; Ekblad, Torun ; Zhong, Nan ; Wichert, Moreno ; Decurtins, Willy ; Nauer, Angela ; Zimmermann, Mauro ; Samain, Florent ; Scheuermann, Jörg and Brown, Peter J , et al. (2015) In Angewandte Chemie (International edition) 54(13). p.31-3927
Abstract

Methods for the rapid and inexpensive discovery of hit compounds are essential for pharmaceutical research and DNA-encoded chemical libraries represent promising tools for this purpose. We here report on the design and synthesis of DAL-100K, a DNA-encoded chemical library containing 103 200 structurally compact compounds. Affinity screening experiments and DNA-sequencing analysis provided ligands with nanomolar affinities to several proteins, including prostate-specific membrane antigen and tankyrase 1. Correlations of sequence counts with binding affinities and potencies of enzyme inhibition were observed and enabled the identification of structural features critical for activity. These results indicate that libraries of this type... (More)

Methods for the rapid and inexpensive discovery of hit compounds are essential for pharmaceutical research and DNA-encoded chemical libraries represent promising tools for this purpose. We here report on the design and synthesis of DAL-100K, a DNA-encoded chemical library containing 103 200 structurally compact compounds. Affinity screening experiments and DNA-sequencing analysis provided ligands with nanomolar affinities to several proteins, including prostate-specific membrane antigen and tankyrase 1. Correlations of sequence counts with binding affinities and potencies of enzyme inhibition were observed and enabled the identification of structural features critical for activity. These results indicate that libraries of this type represent a useful source of small-molecule binders for target proteins of pharmaceutical interest and information on structural features important for binding.

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publishing date
type
Contribution to journal
publication status
published
keywords
DNA/chemistry, DNA Fingerprinting, DNA Probes/chemical synthesis, Enzyme Inhibitors/chemical synthesis, High-Throughput Screening Assays, Humans, Ligands, Prostate-Specific Antigen/drug effects, Serum Albumin/chemistry, Small Molecule Libraries, Structure-Activity Relationship, Tankyrases/antagonists & inhibitors
in
Angewandte Chemie (International edition)
volume
54
issue
13
pages
5 pages
publisher
John Wiley & Sons Inc.
external identifiers
  • scopus:84924914352
  • pmid:25650139
ISSN
1521-3773
DOI
10.1002/anie.201410736
language
English
LU publication?
no
additional info
© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
id
945bf3b9-9dbc-4900-be8a-14f260960b93
date added to LUP
2024-11-21 17:54:20
date last changed
2025-06-21 09:30:05
@article{945bf3b9-9dbc-4900-be8a-14f260960b93,
  abstract     = {{<p>Methods for the rapid and inexpensive discovery of hit compounds are essential for pharmaceutical research and DNA-encoded chemical libraries represent promising tools for this purpose. We here report on the design and synthesis of DAL-100K, a DNA-encoded chemical library containing 103 200 structurally compact compounds. Affinity screening experiments and DNA-sequencing analysis provided ligands with nanomolar affinities to several proteins, including prostate-specific membrane antigen and tankyrase 1. Correlations of sequence counts with binding affinities and potencies of enzyme inhibition were observed and enabled the identification of structural features critical for activity. These results indicate that libraries of this type represent a useful source of small-molecule binders for target proteins of pharmaceutical interest and information on structural features important for binding.</p>}},
  author       = {{Franzini, Raphael M and Ekblad, Torun and Zhong, Nan and Wichert, Moreno and Decurtins, Willy and Nauer, Angela and Zimmermann, Mauro and Samain, Florent and Scheuermann, Jörg and Brown, Peter J and Hall, Jonathan and Gräslund, Susanne and Schüler, Herwig and Neri, Dario}},
  issn         = {{1521-3773}},
  keywords     = {{DNA/chemistry; DNA Fingerprinting; DNA Probes/chemical synthesis; Enzyme Inhibitors/chemical synthesis; High-Throughput Screening Assays; Humans; Ligands; Prostate-Specific Antigen/drug effects; Serum Albumin/chemistry; Small Molecule Libraries; Structure-Activity Relationship; Tankyrases/antagonists & inhibitors}},
  language     = {{eng}},
  month        = {{03}},
  number       = {{13}},
  pages        = {{31--3927}},
  publisher    = {{John Wiley & Sons Inc.}},
  series       = {{Angewandte Chemie (International edition)}},
  title        = {{Identification of structure-activity relationships from screening a structurally compact DNA-encoded chemical library}},
  url          = {{http://dx.doi.org/10.1002/anie.201410736}},
  doi          = {{10.1002/anie.201410736}},
  volume       = {{54}},
  year         = {{2015}},
}