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      Development of a Selection Method for Discovering Irreversible (Covalent) Binders from a DNA-Encoded Library

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          Abstract

          DNA-encoded libraries (DELs) have been broadly applied to identify chemical probes for target validation and lead discovery. To date, the main application of the DEL platform has been the identification of reversible ligands using multiple rounds of affinity selection. Irreversible (covalent) inhibition offers a unique mechanism of action for drug discovery research. In this study, we report a developing method of identifying irreversible (covalent) ligands from DELs. The new method was validated by using 3C protease (3CP) and on-DNA irreversible tool compounds (rupintrivir derivatives) spiked into a library at the same concentration as individual members of that library. After affinity selections against 3CP, the irreversible tool compounds were specifically enriched compared with the library members. In addition, we compared two immobilization methods and concluded that microscale columns packed with the appropriate affinity resin gave higher tool compound recovery than magnetic beads.

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          DNA-encoded chemistry: enabling the deeper sampling of chemical space

          Robert A. Goodnow, Christoph Dumelin, Anthony Keefe (2016)
          DNA-encoded chemistry enables rapid and inexpensive syntheses and screening of vast chemical libraries, and is generating substantial interest and investment in the pharmaceutical industry. Here, Goodnow and colleagues provide an overview of the steps involved in the generation of DNA-encoded libraries, highlighting key applications and future directions for this technology.
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            DNA-Encoded Library Screening Identifies Benzo[b][1,4]oxazepin-4-ones as Highly Potent and Monoselective Receptor Interacting Protein 1 Kinase Inhibitors

            Philip Harris, Bryan King, Deepak Bandyopadhyay … (2016)
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              Small-molecule discovery from DNA-encoded chemical libraries.

              D. Liu, Christoph Dumelin, R Kleiner (2011)
              Researchers seeking to improve the efficiency and cost effectiveness of the bioactive small-molecule discovery process have recently embraced selection-based approaches, which in principle offer much higher throughput and simpler infrastructure requirements compared with traditional small-molecule screening methods. Since selection methods benefit greatly from an information-encoding molecule that can be readily amplified and decoded, several academic and industrial groups have turned to DNA as the basis for library encoding and, in some cases, library synthesis. The resulting DNA-encoded synthetic small-molecule libraries, integrated with the high sensitivity of PCR and the recent development of ultra high-throughput DNA sequencing technology, can be evaluated very rapidly for binding or bond formation with a target of interest while consuming minimal quantities of material and requiring only modest investments of time and equipment. In this tutorial review we describe the development of two classes of approaches for encoding chemical structures and reactivity with DNA: DNA-recorded library synthesis, in which encoding and library synthesis take place separately, and DNA-directed library synthesis, in which DNA both encodes and templates library synthesis. We also describe in vitro selection methods used to evaluate DNA-encoded libraries and summarize successful applications of these approaches to the discovery of bioactive small molecules and novel chemical reactivity.
              Article 0 comments Cited 54 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): SLAS Discov
                Journal ID (iso-abbrev): SLAS Discov
                Journal ID (publisher-id): JBX
                Journal ID (hwp): spjbx
                Title: Slas Discovery
                Publisher: SAGE Publications (Sage CA: Los Angeles, CA )
                ISSN (Print): 2472-5552
                ISSN (Electronic): 2472-5560
                Publication date (Electronic): 1 November 2018
                Publication date (Print): February 2019
                Volume: 24
                Issue: 2
                Pages: 169-174
                Affiliations
                [1 ]GlaxoSmithKline, Cambridge, Massachusetts, USA
                Author notes
                [*]Zhengrong Zhu, Merck Research Laboratories, 2000 Galloping Hill Rd., Kenilworth, NJ 07033, USA. Email: zz3h@ 123456yahoo.com
                Author information
                https://orcid.org/0000-0001-6766-8927
                Article
                Publisher ID: 10.1177_2472555218808454
                DOI: 10.1177/2472555218808454
                PMC ID: 7221453
                PubMed ID: 30383465
                SO-VID: 20b9c6e3-1876-4c9f-9288-faa9634e8c10
                Copyright © © 2018 Society for Laboratory Automation and Screening
                License:

                This article is distributed under the terms of the Creative Commons Attribution 4.0 License ( http://www.creativecommons.org/licenses/by/4.0/) which permits any use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages ( https://us.sagepub.com/en-us/nam/open-access-at-sage).

                History
                Date received : 24 May 2018
                Date revision received : 12 September 2018
                Date accepted : 1 October 2018
                Categories
                Subject: Original Research

                Keywords: dna-encoded library technology,del,dna-encoded chemical libraries,covalent inhibitors,irreversible inhibitors,affinity selections,selection of covalent binders
                Data availability:
                Keywords: dna-encoded library technology, del, dna-encoded chemical libraries, covalent inhibitors, irreversible inhibitors, affinity selections, selection of covalent binders

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