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A DNA-Encoded Library of Chemical Compounds Based on Common Scaffolding Structures Reveals the Impact of Ligand Geometry on Protein Recognition

Favalli, Nicholas ; Biendl, Stefan ; Hartmann, Marco ; Piazzi, Jacopo ; Sladojevich, Filippo ; Gräslund, Susanne ; Brown, Peter J ; Näreoja, Katja ; Schüler, Herwig LU orcid and Scheuermann, Jörg , et al. (2018) In ChemMedChem 13(13). p.1303-1307
Abstract

A DNA-encoded chemical library (DECL) with 1.2 million compounds was synthesized by combinatorial reaction of seven central scaffolds with two sets of 343×492 building blocks. Library screening by affinity capture revealed that for some target proteins, the chemical nature of building blocks dominated the selection results, whereas for other proteins, the central scaffold also crucially contributed to ligand affinity. Molecules based on a 3,5-bis(aminomethyl)benzoic acid core structure were found to bind human serum albumin with a Kd value of 6 nm, while compounds with the same substituents on an equidistant but flexible l-lysine scaffold showed 140-fold lower affinity. A 18 nm tankyrase-1 binder featured l-lysine as linking moiety,... (More)

A DNA-encoded chemical library (DECL) with 1.2 million compounds was synthesized by combinatorial reaction of seven central scaffolds with two sets of 343×492 building blocks. Library screening by affinity capture revealed that for some target proteins, the chemical nature of building blocks dominated the selection results, whereas for other proteins, the central scaffold also crucially contributed to ligand affinity. Molecules based on a 3,5-bis(aminomethyl)benzoic acid core structure were found to bind human serum albumin with a Kd value of 6 nm, while compounds with the same substituents on an equidistant but flexible l-lysine scaffold showed 140-fold lower affinity. A 18 nm tankyrase-1 binder featured l-lysine as linking moiety, while molecules based on d-Lysine or (2S,4S)-amino-l-proline showed no detectable binding to the target. This work suggests that central scaffolds which predispose the orientation of chemical building blocks toward the protein target may enhance the screening productivity of encoded libraries.

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publishing date
type
Contribution to journal
publication status
published
keywords
Antigens, Neoplasm/metabolism, Carbonic Anhydrase IX/metabolism, DNA/chemistry, Humans, Ligands, Molecular Structure, Protein Binding, Serum Albumin, Human/metabolism, Small Molecule Libraries/chemistry, Tankyrases/metabolism
in
ChemMedChem
volume
13
issue
13
pages
5 pages
publisher
Wiley-Blackwell
external identifiers
  • pmid:29856130
  • scopus:85049566454
ISSN
1860-7187
DOI
10.1002/cmdc.201800193
language
English
LU publication?
no
additional info
© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
id
f76f6207-1a25-44a6-a754-a01438198fd3
date added to LUP
2024-11-21 17:49:22
date last changed
2025-06-20 21:09:12
@article{f76f6207-1a25-44a6-a754-a01438198fd3,
  abstract     = {{<p>A DNA-encoded chemical library (DECL) with 1.2 million compounds was synthesized by combinatorial reaction of seven central scaffolds with two sets of 343×492 building blocks. Library screening by affinity capture revealed that for some target proteins, the chemical nature of building blocks dominated the selection results, whereas for other proteins, the central scaffold also crucially contributed to ligand affinity. Molecules based on a 3,5-bis(aminomethyl)benzoic acid core structure were found to bind human serum albumin with a Kd value of 6 nm, while compounds with the same substituents on an equidistant but flexible l-lysine scaffold showed 140-fold lower affinity. A 18 nm tankyrase-1 binder featured l-lysine as linking moiety, while molecules based on d-Lysine or (2S,4S)-amino-l-proline showed no detectable binding to the target. This work suggests that central scaffolds which predispose the orientation of chemical building blocks toward the protein target may enhance the screening productivity of encoded libraries.</p>}},
  author       = {{Favalli, Nicholas and Biendl, Stefan and Hartmann, Marco and Piazzi, Jacopo and Sladojevich, Filippo and Gräslund, Susanne and Brown, Peter J and Näreoja, Katja and Schüler, Herwig and Scheuermann, Jörg and Franzini, Raphael and Neri, Dario}},
  issn         = {{1860-7187}},
  keywords     = {{Antigens, Neoplasm/metabolism; Carbonic Anhydrase IX/metabolism; DNA/chemistry; Humans; Ligands; Molecular Structure; Protein Binding; Serum Albumin, Human/metabolism; Small Molecule Libraries/chemistry; Tankyrases/metabolism}},
  language     = {{eng}},
  month        = {{07}},
  number       = {{13}},
  pages        = {{1303--1307}},
  publisher    = {{Wiley-Blackwell}},
  series       = {{ChemMedChem}},
  title        = {{A DNA-Encoded Library of Chemical Compounds Based on Common Scaffolding Structures Reveals the Impact of Ligand Geometry on Protein Recognition}},
  url          = {{http://dx.doi.org/10.1002/cmdc.201800193}},
  doi          = {{10.1002/cmdc.201800193}},
  volume       = {{13}},
  year         = {{2018}},
}