Chemical composition of DNA-encoded libraries, past present and future

Dickson, Paige; Kodadek, Thomas

doi:10.1039/c9ob00581a

“…Achieving efficient chemical transformations on-DNA is not a trivial matter. [56][57][58][59][60] The idiosyncratic nature of the encoding DNA results in reaction requirements that are incompatible with a significant portion of the conventional medicinal chemistry toolbox. These requirements include (i) an aqueous environment as DNA is insoluble in organic solvents, (ii) highly dilute conditions for solubility considerations, and (iii) exquisite chemoselectivity to avoid damaging the functional group rich DNA tag.…”

Section: Dna Compatible Chemistrymentioning

confidence: 99%

DNA Encoded Libraries: A Visitor's Guide

Flood

¹

,

Kingston

²

,

Vantourout

³

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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“…54 The inhibition of KRas has been widely investigated for the development of oncology therapeutics, however, due to the lack of well-defined binding pockets on the protein it has proved extremely challenging to develop potent ligands. [54][55][56][57] Some success has been reported using fragment screening, which enabled Protein and PhABit are incubated with increasing concentrations of competitive inhibitor before UV irradiation and analysis by intact MS. B: Elaborated compounds were generated from a similarity search on nine hit PhABits (1)(2)(3)(4)(5)(6)(7)(8)(9). These were screened at a single concentration (100 µM) to identify 40 hit compounds that showed >50% inhibition of crosslinking of 2 to BRD4-BD1.…”

Section: Application To Other Targetsmentioning

confidence: 99%

“…Several clustering methods were tested and two selected for use: Jarvis-Patrick algorithm with a path-based fingerprint (ChemAxon FP7), and 2D topological pharmacophore fingerprints (ProSAR implemented within MOE, with the actinium atom defining the attachment point). [6][7][8][9] Clusters were examined and building blocks considered to add no value were removed. Re-clustering was then performed and one or two compounds selected from each cluster, usually the smallest or simplest, resulting in a list of 470 diverse amines and 281…”

Section: Selection Of Amine Functionalised Fragmentsmentioning

confidence: 99%

“…6 Bindingdriven assays, such as Affinity Selection Mass Spectrometry (ASMS) and DNA Encoded Libraries (DELs) have recently been developed to accelerate ligand discovery through the efficient screening of large libraries (10 6 -10 12 compounds). [7][8][9][10][11][12][13][14][15][16] While these approaches are powerful, they employ lead-like libraries (MW>300) that generate hits that may suffer from sub-optimal ligand efficiency and can prove challenging to optimise. Additionally, the upfront investment in library generation, and sample handling, limits the accessibility of this screening strategy to the broader scientific community.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

PhotoAffinity Bits: A Photoaffinity-Based Fragment Screening Platform for Efficient Identification of Protein Ligands

Grant

¹

,

Fallon²,

Hann

³

et al. 2020

Preprint

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Advances in genomic analyses enable the identification of new proteins that are associated with disease. To validate these targets, tool molecules are required to demonstrate that a ligand can have a disease-modifying effect. Currently, as tools are reported for only a fraction of the proteome, platforms for ligand discovery are essential to leverage insights from genomic analyses. Fragment screening offers an efficient approach to explore chemical space, however, it remains challenging to develop techniques that are both sufficiently high-throughput and sensitive. We present a fragment screening platform, termed PhABits (PhotoAffinity Bits), which utilises a library of photoreactive fragments to covalently capture fragment-protein interactions. Hits can be profiled to determine potency and site of crosslinking, and subsequently developed as reporters in a competitive displacement assay to identify novel hit matter. We envision that the PhABits will be widely applicable to novel protein targets, identifying starting points in the development of therapeutics.

show abstract

“…6 Bindingdriven assays, such as Affinity Selection Mass Spectrometry (ASMS) and DNA Encoded Libraries (DELs) have recently been developed to accelerate ligand discovery through the efficient screening of large libraries (10 6 -10 12 compounds). [7][8][9][10][11][12][13][14][15][16] While these approaches are powerful, they employ lead-like libraries (MW>300) that generate hits that may suffer from sub-optimal ligand efficiency and can prove challenging to optimise. Additionally, the upfront investment in library generation, and sample handling, limits the accessibility of this screening strategy to the broader scientific community.…”

Section: Introductionmentioning

confidence: 99%

PhotoAffinity Bits: A Photoaffinity-Based Fragment Screening Platform for Efficient Identification of Protein Ligands

grant¹,

fallon²,

hann³

et al. 2020

Preprint

View full text Add to dashboard Cite

Advances in genomic analyses enable the identification of new proteins that are associated with disease. To validate these targets, tool molecules are required to demonstrate that a ligand can have a disease-modifying effect. Currently, as tools are reported for only a fraction of the proteome, platforms for ligand discovery are essential to leverage insights from genomic analyses. Fragment screening offers an efficient approach to explore chemical space, however, it remains challenging to develop techniques that are both sufficiently high-throughput and sensitive. We present a fragment screening platform, termed PhABits (PhotoAffinity Bits), which utilises a library of photoreactive fragments to covalently capture fragment-protein interactions. Hits can be profiled to determine potency and site of crosslinking, and subsequently developed as reporters in a competitive displacement assay to identify novel hit matter. We envision that the PhABits will be widely applicable to novel protein targets, identifying starting points in the development of therapeutics.

show abstract

Chemical composition of DNA-encoded libraries, past present and future

Abstract: We discuss here the chemical composition of DNA-encoded libraries likely to be made in the near future.

Cited by 93 publications

References 86 publications

DNA Encoded Libraries: A Visitor's Guide

DNA Encoded Libraries: A Visitor's Guide

PhotoAffinity Bits: A Photoaffinity-Based Fragment Screening Platform for Efficient Identification of Protein Ligands

PhotoAffinity Bits: A Photoaffinity-Based Fragment Screening Platform for Efficient Identification of Protein Ligands

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