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The Impact of Variable Selection Coverage on Detection of Ligands from a DNA-Encoded Library Screen
Kelly A McCarthy1, G Joseph Franklin1, David R Lancia1
1FORMA Therapeutics, Watertown, MA, USA.
SLAS Discovery : Advancing Life Sciences R & D
|February 29, 2020
Summary
DNA-encoded library (DEL) screening requires careful consideration of sequencing depth and compound input. Insufficient sequencing can obscure valuable ligands, potentially hindering drug discovery efforts.
Area of Science:
- Medicinal Chemistry
- Chemical Biology
- Drug Discovery
Background:
- DNA-encoded library (DEL) technology enables screening of vast compound libraries for drug discovery.
- Numerous successes have been reported, but factors influencing screen success require rigorous examination.
Purpose of the Study:
- To investigate the impact of sequencing depth and initial compound input on DEL screen outcomes.
- To assess the influence of these variables on detecting compounds with known target affinities.
Main Methods:
- Exploration of variable sample sequencing depth.
- Simultaneous probing of initial compound input effects.
- Analysis of sequencing data to identify tool compounds and potential ligands.
Main Results:
- High-affinity compounds can be identified from DEL screens.
- A mismatch between selection output and sequencing quantity can mask useful ligands.
- Selection coverage is crucial for comprehensive DEL screen analysis.
Conclusions:
- Inadequate sequencing depth can suppress signals from weak or underrepresented ligands.
- Missed ligands due to sequencing limitations may critically impact drug discovery programs.
- Optimizing sequencing strategy is vital for maximizing DEL screening success.
