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Updated: Jun 24, 2026

Competitive Genomic Screens of Barcoded Yeast Libraries

Competitive Genomic Screens of Barcoded Yeast Libraries

Published on: August 11, 2011

Off-DNA DNA-Encoded Library Affinity Screening.

Amber L Hackler, Forrest G FitzGerald, Vuong Q Dang

¹Roche Pharma Research and Early Development (pRED) , Roche Innovation Center Basel Hoffman-La Roche Ltd , Grenzacherstrasse 124 , CH-4070 Basel , Switzerland.

ACS Combinatorial Science

|December 13, 2019

Summary

This summary is machine-generated.

This study introduces off-DNA screening for DNA-encoded libraries (DELs), separating small molecules from DNA tags to prevent interference. This novel method enhances drug discovery by enabling accurate target binding detection using fluorescence polarization.

Keywords:

DNA-encoded library fluorescence anisotropy high-throughput screening microfluidics miniaturization one-bead-one-compound

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Area of Science:

Biochemistry
Medicinal Chemistry
Drug Discovery

Background:

DNA-encoded library (DEL) technology is a powerful tool for small molecule discovery.
Conventional on-DNA screening methods can be hindered by DNA tag interference with target binding.
Developing new screening strategies is crucial for expanding DEL applications.

Purpose of the Study:

To develop and validate an off-DNA screening approach for DELs.
To eliminate DNA tag interference in DEL screening experiments.
To demonstrate the utility of off-DNA screening for identifying small molecule ligands.

Main Methods:

Utilized solid-phase DEL and droplet-based microfluidics for screening.
Separated DEL members from their DNA tags (off-DNA screening).
Employed in-droplet laser-induced fluorescence polarization (FP) for target binding detection.

Main Results:

Successfully screened a 67,100-member DEL against discoidin domain receptor 1 (DDR1).
Identified known receptor tyrosine kinase (RTK) inhibitor pharmacophores, including azaindole and quinazolinone derivatives.
Demonstrated the feasibility of off-DNA screening with FP detection.

Conclusions:

Off-DNA DEL screening with FP detection overcomes DNA tag interference issues.
This method is applicable to diverse target classes, including challenging proteins.
The approach holds significant potential for advancing small molecule drug discovery.