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

Angew Chem Int Ed Engl. 2015 Mar 23;54(13):3927-31. doi: 10.1002/anie.201410736. Epub 2015 Feb 3.


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.

Keywords: combinatorial chemistry; drug discovery; encoded libraries; high-throughput screening; structure-activity relationships.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • DNA / chemistry*
  • DNA Fingerprinting
  • DNA Probes / chemical synthesis*
  • DNA Probes / chemistry
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / pharmacology
  • High-Throughput Screening Assays
  • Humans
  • Ligands
  • Prostate-Specific Antigen / drug effects
  • Serum Albumin / chemistry
  • Small Molecule Libraries
  • Structure-Activity Relationship
  • Tankyrases / antagonists & inhibitors


  • DNA Probes
  • Enzyme Inhibitors
  • Ligands
  • Serum Albumin
  • Small Molecule Libraries
  • DNA
  • Tankyrases
  • TNKS protein, human
  • Prostate-Specific Antigen