The Impact of Variable Selection Coverage on Detection of Ligands from a DNA-Encoded Library Screen. (June 2020)

• Record Type: Journal Article
• Authors: McCarthy, Kelly A.; Franklin, G. Joseph; Lancia, David R.; Olbrot, Martin; Pardo, Eneida; O'Connell, Jonathan C.; Kollmann, Christopher S.
• Is Part Of: SLAS discovery. Volume 25:Number 5(2020)
• Page Start: 515
• Page End: 522
• Publication Date: 2020-06
• Subjects: DNA-encoded library -- DEL -- drug discovery -- selection -- hit identification; Drugs -- Analysis -- Periodicals; Drugs -- Testing -- Periodicals; Biomolecules -- Analysis -- Periodicals; Biomolecules -- Analysis; Drugs -- Analysis; Drugs -- Testing; Drug Evaluation, Preclinical; Molecular Biology -- methods; Periodicals; Periodicals; 615.1
• DOI: 10.1177/2472555220908240
• Languages: English
• ISSNs: 2472-5552

Abstract

DNA-encoded library (DEL) technology has become a prominent screening platform in drug discovery owing to the capacity to screen billions or trillions of compounds in a single experiment. Although numerous successes with DEL technology have been reported, we are unaware of a rigorous examination of the many different variables that can influence a screen's success. Herein, we explore the impact of variable sample sequencing depth on the detection of tool compounds with known affinities toward a given target while simultaneously probing the effect of initial compound input. Our sequencing data confirm reports that high-affinity compounds can be discovered directly from a DEL screen, but we demonstrate that a mismatch between selection output and sequencing quantity can obscure useful ligands. Our results highlight the importance of selection coverage in grasping the entire picture of a DEL screen where the signal of a weak or underrepresented ligand may be suppressed by the inherent noise of a selection. These potential missed ligands may be critical to the success or failure of a drug discovery program.