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Area of Science:

  • Medicinal Chemistry
  • Biochemistry
  • Drug Discovery Technology

Background:

  • Affinity-selection platforms are crucial for early drug discovery.
  • Current DNA-encoded libraries (DELs) face limitations in synthesis and target compatibility.

Purpose of the Study:

  • To introduce a novel barcode-free self-encoded library (SEL) platform for high-throughput screening.
  • To overcome the limitations of existing technologies, particularly for nucleic acid-binding targets.

Main Methods:

  • Development of SELs enabling direct screening of over 500,000 small molecules.
  • Integration of tandem mass spectrometry with custom software for automated structure annotation.
  • Establishment of efficient, high-diversity synthesis protocols for diverse chemical scaffolds.

Main Results:

  • Successful affinity selection screening against carbonic anhydrase IX, identifying multiple nanomolar binders.
  • Discovery of potent inhibitors for flap endonuclease 1 (FEN1), a DNA-processing enzyme.
  • Demonstration of SELs' capability to screen large libraries in a single experiment.

Conclusions:

  • The SEL platform offers a powerful, tag-free alternative for screening large chemical libraries.
  • This technology expands drug discovery capabilities to novel target classes, including DNA-processing enzymes.
  • SELs represent a significant advancement for both academic and industrial early drug discovery efforts.