Quantitative Comparison of Enrichment from DNA-Encoded Chemical Library Selections

Overview

Journal ACS Comb Sci

Publisher American Chemical Society

Specialty Chemistry

Date 2019 Jan 24

PMID 30672692

Citations 26

Authors

John C Faver

Kevin Riehle

David R Lancia Jr

Jared B J Milbank

Christopher S Kollmann

Nicholas Simmons

Zhifeng Yu

Martin M Matzuk

Affiliations

Soon will be listed here.

Abstract

DNA-encoded chemical libraries (DELs) provide a high-throughput and cost-effective route for screening billions of unique molecules for binding affinity for diverse protein targets. Identifying candidate compounds from these libraries involves affinity selection, DNA sequencing, and measuring enrichment in a sample pool of DNA barcodes. Successful detection of potent binders is affected by many factors, including selection parameters, chemical yields, library amplification, sequencing depth, sequencing errors, library sizes, and the chosen enrichment metric. To date, there has not been a clear consensus about how enrichment from DEL selections should be measured or reported. We propose a normalized z-score enrichment metric using a binomial distribution model that satisfies important criteria that are relevant for analysis of DEL selection data. The introduced metric is robust with respect to library diversity and sampling and allows for quantitative comparisons of enrichment of n-synthons from parallel DEL selections. These features enable a comparative enrichment analysis strategy that can provide valuable information about hit compounds in early stage drug discovery.

Citing Articles

Open-Source DNA-Encoded Library Package for Design, Decoding and Analysis: DELi.

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Identification of Structurally Novel KRAS Inhibitors through Covalent DNA-Encoded Library Screening.

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The long road of drug development for endometriosis - Pains, gains, and hopes.

Liao Z, Monsivais D, Matzuk M J Control Release. 2024; 376:429-440.

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Identification of potent pan-ephrin receptor kinase inhibitors using DNA-encoded chemistry technology.

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