Journal
CHEMMEDCHEM
Volume 13, Issue 13, Pages 1303-1307Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.201800193
Keywords
bifunctional ligands; DNA-encoded chemical libraries; human serum albumin; tankyrase-1
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Funding
- ETH Zurich
- Swiss National Science Foundation [310030B_163479]
- Sinergia [CRS112_160699]
- ERC Advanced Grant ZAUBERKUGEL [670603]
- AbbVie [1097737]
- Bayer Pharma AG
- Boehringer Ingelheim
- Canada Foundation for Innovation
- Eshelman Institute for Innovation
- Genome Canada
- Innovative Medicines Initiative (EU/EFPIA) (ULTRA-DD grant) [115766]
- Janssen
- Merck Co.
- Novartis Pharma AG
- Ontario Ministry of Economic Development and Innovation
- Pfizer
- Sao Paulo Research Foundation-FAPESP
- Takeda
- Wellcome Trust
- Swiss National Science Foundation (SNF) [310030B_163479] Funding Source: Swiss National Science Foundation (SNF)
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A DNA-encoded chemical library (DECL) with 1.2 million compounds was synthesized by combinatorial reaction of seven central scaffolds with two sets of 343x492 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 K-d value of 6nm, while compounds with the same substituents on an equidistant but flexible l-lysine scaffold showed 140-fold lower affinity. A 18nm 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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