title: Identification of structure-activity relationships from screening a structurally compact DNA-encoded chemical library.
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 represent a useful source of small-molecule binders for target proteins of pharmaceutical interest and information on structural features important for binding.
authors: Institute of Pharmaceutical Sciences, ETH Zürich, 8093 Zürich (Switzerland).
authors: Raphael M
authors: RM
authors: Franzini
authors: Torun
authors: T
authors: Ekblad
authors: Nan
authors: N
authors: Zhong
authors: Moreno
authors: M
authors: Wichert
authors: Willy
authors: W
authors: Decurtins
authors: Angela
authors: A
authors: Nauer
authors: Mauro
authors: M
authors: Zimmermann
authors: Florent
authors: F
authors: Samain
authors: Jörg
authors: J
authors: Scheuermann
authors: Peter J
authors: PJ
authors: Brown
authors: Jonathan
authors: J
authors: Hall
authors: Susanne
authors: S
authors: Gräslund
authors: Herwig
authors: H
authors: Schüler
authors: Dario
authors: D
authors: Neri
mesh_terms: D004247:DNA / Q000737:chemistry*; D016172:DNA Fingerprinting; D015342:DNA Probes / Q000138:chemical synthesis* / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D057166:High-Throughput Screening Assays; D006801:Humans; D008024:Ligands; D017430:Prostate-Specific Antigen / Q000187:drug effects; D012709:Serum Albumin / Q000737:chemistry; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship; D038501:Tankyrases / Q000037:antagonists & inhibitors
chemical_list: D004247:DNA; D015342:DNA Probes; D004791:Enzyme Inhibitors; D008024:Ligands; D017430:Prostate-Specific Antigen; D012709:Serum Albumin; D054852:Small Molecule Libraries; D038501:Tankyrases; C418109:TNKS protein, human
keywords: combinatorial chemistry; drug discovery; encoded libraries; high-throughput screening; structure-activity relationships