Future challenges with DNA-encoded chemical libraries in the drug discovery domain

Zhao, Guixian; Huang, Yiran; Zhou, Yu; Li, Yizhou; Li, Xiaoyü

doi:10.1080/17460441.2019.1614559

Cited by 76 publications

(54 citation statements)

References 143 publications

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“…DNA encoded libraries (DEL) have become a valuable part of the hit identification repertoire. The power of DEL lies in the ability to screen billions of small molecules, for affinity, against a molecular target of interest, all at once, in a single tube . This technology has the potential to democratize the processes of drug discovery by providing an alternate route to high‐throughput screening which currently requires cost intensive, specialized facilities .…”

Section: Figurementioning

confidence: 99%

“…The power of DEL lies in the ability to screen billions of small molecules, for affinity, against a molecular target of interest, all at once, in a single tube . This technology has the potential to democratize the processes of drug discovery by providing an alternate route to high‐throughput screening which currently requires cost intensive, specialized facilities . Although DEL has proven valuable, the idiosyncratic nature of the DNA tag (which is not soluble in organic solvents and rich in functional groups) limit both the synthetic toolbox available to elaborate the small molecule library members and the resulting molecular diversity of the libraries produced .…”

Section: Figurementioning

confidence: 99%

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RASS‐Enabled S/P−C and S−N Bond Formation for DEL Synthesis

Flood

Zhang

et al. 2020

Angew Chem Int Ed

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DNA encoded libraries (DEL) have shown promise as a valuable technology for democratizing the hit discovery process. Although DEL provides relatively inexpensive access to libraries of unprecedented size, their production has been hampered by the idiosyncratic needs of the encoding DNA tag relegating DEL compatible chemistry to dilute aqueous environments. Recently reversible adsorption to solid support (RASS) has been demonstrated as a promising method to expand DEL reactivity using standard organic synthesis protocols. Here we demonstrate a suite of on‐DNA chemistries to incorporate medicinally relevant and C−S, C−P and N−S linkages into DELs, which are underrepresented in the canonical methods.

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Section: Figurementioning

confidence: 99%

Section: Figurementioning

confidence: 99%

RASS‐Enabled S/P−C and S−N Bond Formation for DEL Synthesis

Flood

Zhang

et al. 2020

Angew Chem Int Ed

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“…1a) 18,19 . Chemical combinatorial methods, such as DNA-encoded libraries (DELs) 20,21 and one-bead-one-compound (OBOC) libraries 22,23 , can easily overcome this hurdle; however, each of these techniques faces its own limitations. DELs are typically limited to three or four varied positions, due to inefficiencies in the chemistry used for their assembly, and as such are more often categorized as libraries of small molecules.…”

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confidence: 99%

Ultra-large chemical libraries for the discovery of high-affinity peptide binders

et al. 2020

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High-diversity genetically-encoded combinatorial libraries (10 8 −10 13 members) are a rich source of peptide-based binding molecules, identified by affinity selection. Synthetic libraries can access broader chemical space, but typically examine only~10 6 compounds by screening. Here we show that in-solution affinity selection can be interfaced with nano-liquid chromatography-tandem mass spectrometry peptide sequencing to identify binders from fully randomized synthetic libraries of 10 8 members-a 100-fold gain in diversity over standard practice. To validate this approach, we show that binders to a monoclonal antibody are identified in proportion to library diversity, as diversity is increased from 10 6-10 8. These results are then applied to the discovery of p53-like binders to MDM2, and to a family of 3-19 nM-affinity, α/β-peptide-based binders to 14-3-3. An X-ray structure of one of these binders in complex with 14-3-3σ is determined, illustrating the role of β-amino acids in facilitating a key binding contact.

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“…Several cycles of affinity selection, typically involving an immobilized target protein and a pool of libraries, yield a mixture of compounds enriched in binders to the protein of interest. Amplification of the DNA region by polymer chain reaction methods and posterior next generation sequencing permits the identification of the structure of the binding molecules [3][4][5][6][7][8] .…”

mentioning

confidence: 99%

“…The progress achieved in this field during the last two decades has transformed DEL to a powerful production tool for most pharmaceutical companies to identify new ligands for both novel and traditional biological targets [2][3][4][5][8][9][10][11][12][13] . Despite of this, a remaining challenge for DEL is achieving the right balance of library size and molecular properties.…”

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confidence: 99%

Navigating the DNA encoded libraries chemical space

2020

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DNA-encoded library (DEL) technology is a novel ligand identification strategy that allows the synthesis and screening of unprecedented chemical diversity more efficiently than conventional methods. However, no reports have been published to systematically study how to increase the diversity and improve the molecular property space that can be covered with DEL. This report describes the development and application of eDESIGNER, an algorithm that comprehensively generates all possible library designs, enumerates and profiles samples from each library and evaluates them to select the libraries to be synthesized. This tool utilizes suitable on-DNA chemistries and available building blocks to design and identify libraries with a pre-defined molecular weight distribution and maximal diversity compared with compound collections from other sources.

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Future challenges with DNA-encoded chemical libraries in the drug discovery domain

Cited by 76 publications

References 143 publications

RASS‐Enabled S/P−C and S−N Bond Formation for DEL Synthesis

RASS‐Enabled S/P−C and S−N Bond Formation for DEL Synthesis

Ultra-large chemical libraries for the discovery of high-affinity peptide binders

Navigating the DNA encoded libraries chemical space

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