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Dose-Response Activity-Based DNA-Encoded Library Screening.

Patrick R Fitzgerald1, Wesley G Cochrane2, Brian M Paegel2,3

  • 1Skaggs Doctoral Program in the Chemical and Biological Sciences, Scripps Research, La Jolla, California 92037, United States.

ACS Medicinal Chemistry Letters
|September 22, 2023
PubMed
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This study introduces dose-response DNA-encoded library (DEL) screening using photocleavage. This method confirms screening hits by demonstrating photochemical dose-dependent responses, improving drug discovery efficiency.

Area of Science:

  • Biochemistry
  • Medicinal Chemistry
  • Drug Discovery

Background:

  • Dose-response data enhances confidence in screening hit authenticity.
  • DNA-encoded library (DEL) screening is a powerful tool for identifying small molecule modulators of biological targets.
  • Photochemical methods offer precise control over compound release and concentration.

Purpose of the Study:

  • To demonstrate dose-response solid-phase DNA-encoded library (DEL) screening.
  • To validate the utility of photochemical dose-response DEL screening for prioritizing drug leads.
  • To assess the hit rates and identify inhibitors against factor Xa (FXa) and autotaxin (ATX) using this novel screening approach.

Main Methods:

  • A 55,296-member DNA-encoded library (DEL) was screened using photocleavage-induced compound release.

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  • Compound dose was modulated by varying UV intensity in microfluidic droplets.
  • Screening was performed against model enzyme drug targets: factor Xa (FXa) and autotaxin (ATX).

    • Main Results:

    • Photochemical dose-dependent hit rates were observed for both FXa and ATX screens.
    • FXa hits included structures consistent with known inhibitors, with four compounds exhibiting inhibitory activity (IC50 values ranging from 4.2 to 19 μM).
    • Top ATX hits, including dihydrobenzamidazolones and a tetrahydroisoquinoline, were validated as inhibitors (IC50 values ranging from 1 to 13 μM).

    Conclusions:

    • Photochemical dose-response DEL screening effectively prioritizes hits for synthesis.
    • This method enhances the efficiency of lead identification in DEL campaigns.
    • The demonstrated dose-response capability increases confidence in the authenticity of identified hits.