Dose-Response Activity-Based DNA-Encoded Library Screening

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.
• 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.