Second generation DNA-encoded dynamic combinatorial chemical libraries

Reddavide, Francesco V.; Cui, Meiying; Lin, Weilin; Fu, Naiqiang; Heiden, Stephan; Andrade, Helena; Thompson, Michael C.; Zhang, Yixin

doi:10.1039/c9cc01429b

Cited by 45 publications

(33 citation statements)

References 38 publications

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“…Another interesting advance in the ESAC is the development of dynamic self-assembling libraries. [30,31] These libraries are created in a similar manner to the typical ESAC described above, but the hybridization region is short and only forms unstable duplexed species that readily convert under dynamic combinatorial control. Upon external influence, such as introduction of the target protein, the library will shift its equilibrium in reaction to the binding events that stabilize the dynamic duplexed interactions.…”

Section: Alternative Methods For Del Formationmentioning

confidence: 99%

“…Upon hybridization, the attached small molecule fragments do not react (to create a single ligand) and hence this is referred to as dual pharmacophore library. Another interesting advance in the ESAC is the development of dynamic self‐assembling libraries . These libraries are created in a similar manner to the typical ESAC described above, but the hybridization region is short and only forms unstable duplexed species that readily convert under dynamic combinatorial control.…”

Section: Alternative Methods For Del Formationmentioning

confidence: 99%

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DNA Encoded Libraries: A Visitor's Guide

Flood

Kingston

Vantourout

et al. 2020

Israel Journal of Chemistry

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In 1992, Brenner and Lerner hypothesized that individual chemical transformations could be encoded in DNA, allowing the rapid synthesis and screening of large collections of small molecules. Since their report, huge investments into the development of the DNA encoded library (DEL) technology have enabled the acceleration of the drug discovery process especially early phase discovery undertakings such as target validation and hit identification. As DEL lies at the nexus between chemistry and biology, there is an increasing need to expand the toolboxes of both organic transformations and biological methods. However, the myriad of techniques and reactions already reported can be difficult to digest for practitioners whose expertise resides outside the realm of DEL. This review therefore focuses on a stepwise presentation of DEL from the basic concepts to newest developments. The presentation includes the history, fundamentals, and successes of DEL, different methods for DEL synthesis and affinity selection, the conventional transformations, and finally the latest developments from a synthetic organic perspective.

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Section: Alternative Methods For Del Formationmentioning

confidence: 99%

Section: Alternative Methods For Del Formationmentioning

confidence: 99%

DNA Encoded Libraries: A Visitor's Guide

Flood

Kingston

Vantourout

et al. 2020

Israel Journal of Chemistry

View full text Add to dashboard Cite

show abstract

“…The integration of these two concepts was lately elaborated into a number of DNA‐encoded dynamic libraries (DEDL) methods by Zhang, [67] Winssinger, [68] and us [12,69] . With dynamic DELs, non‐immobilized target promotes the formation of DNA duplexes (Figure 4a) or 3‐way junctions of the ligand pairs (Figure 4b), which could be further enriched by thermal reshuffling [67a] or irreversibly captured by photo‐crosslinking [12c,d,69] or enzymatic ligation [67b] . The crosslinked DNA duplexes or 3‐way junctions could be selectively PCR‐amplified to identify the fragment pairs that bind to the target cooperatively.…”

Section: Selection With Non‐immobilized Targetsmentioning

confidence: 99%

Recent Advances on the Selection Methods of DNA‐Encoded Libraries

Huang

2021

ChemBioChem

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DNA-encoded libraries (DEL) have come of age and become a major technology platform for ligand discovery in both academia and the pharmaceutical industry. Technological maturation in the past two decades and the recent explosive developments of DEL-compatible chemistries have greatly improved the chemical diversity of DELs and fueled its applications in drug discovery. A relatively less-covered aspect of DELs is the selection method. Typically, DEL selection is considered as a binding assay and the selection is conducted with purified protein targets immobilized on a matrix, and the binders are separated from the non-binding background via physical washes. However, the recent innovations in DEL selection methods have not only expanded the target scope of DELs, but also revealed the potential of the DEL technology as a powerful tool in exploring fundamental biology. In this Review, we first cover the "classic" DEL selection methods with purified proteins on solid phase, and then we discuss the strategies to realize DEL selections in solution phase. Finally, we focus on the emerging approaches for DELs to interrogate complex biological targets.

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“…Encoded dynamic combinatorial chemical libraries (Figure 2f) make use of DNA‐mediated hybridization of relatively “unstable” duplex DNA oligonucleotides that can be re‐paired upon target addition to enrich high affinity fragment combinations [68,69] . Freezing the thermodynamic equilibrium was facilitated, for example, by photo‐crosslinking or ligation of DNA oligonucleotides [70,71] …”

Section: Encoded Librariesmentioning

confidence: 99%

Scanning Protein Surfaces with DNA‐Encoded Libraries

et al. 2020

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Understanding the ligandability of a target protein, defined as the capability of a protein to bind drug‐like compounds on any site, can give important stimuli to drug‐development projects. For instance, inhibition of protein–protein interactions usually depends on the identification of protein surface binders. DNA‐encoded chemical libraries (DELs) allow scanning of protein surfaces with large chemical space. Encoded library selection screens uncovered several protein–protein interaction inhibitors and compounds binding to the surface of G protein‐coupled receptors (GPCRs) and kinases. The protein surface‐binding chemotypes from DELs are predominantly chemically modified and cyclized peptides, and functional small‐molecule peptidomimetics. Peptoid libraries and structural peptidomimetics have been less studied in the DEL field, hinting at hitherto less populated chemical space and suggesting alternative library designs. Roughly a third of bioactive molecules evolved from smaller, target‐focused libraries. They showcase the potential of encoded libraries to identify more potent molecules from weak, for example, fragment‐like, starting points.

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Second generation DNA-encoded dynamic combinatorial chemical libraries

Abstract: A novel DNA-encoded chemical library architecture can mimic the mechanisms of immunity to evolve binders through recombination, dynamics and adaption.

Cited by 45 publications

References 38 publications

DNA Encoded Libraries: A Visitor's Guide

DNA Encoded Libraries: A Visitor's Guide

Recent Advances on the Selection Methods of DNA‐Encoded Libraries

Scanning Protein Surfaces with DNA‐Encoded Libraries

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