Advancements in DEL-Compatible Chemical Reactions

Anderson, Matthew; Castan, Isaline F.S.F.; Graham, Jessica S.; Mahmoud, Haitham H.; Odger, Jake; Salvini, Catherine L.A.; Taylor, Cameron; Waring, Michael J.

doi:10.1007/7355_2022_151

Cited by 3 publications

(2 citation statements)

References 82 publications

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“…The correspondence between the chemical structure information and the DNA barcode sequence is essential to library selection and hit decoding (Figure ). Therefore, preserving the information stored within the DNA barcodes during DEL construction is an essential requirement of DNA-compatible chemistry . Chemical transformations in DEL synthesis need robustness, and reactions that cause DNA damage must be avoided. , If the integrity of the DNA tag is compromised, it can undermine coding fidelity and lead to false hit identification in the decoding process by next-generation sequencing (NGS) …”

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confidence: 99%

Comparative Study of DNA Barcode Integrity Evaluation Approaches in the Early-Stage Development of DNA-Compatible Chemical Transformation

Wang,

Zhao,

Zhang

et al. 2023

ACS Pharmacol. Transl. Sci.

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DNA-encoded libraries (DEL) have emerged as an important drug discovery technical platform for target-based compound library selection. The success rate of DEL depends on both the chemical diversity of combinatorial libraries and the accuracy of DNA barcoding. Therefore, it is critical that the chemistry applied to library construction should efficiently transform on a wide range of substrates while preserving the integrity of DNA tags. Although several analytical methods have been developed to measure DNA damage caused by DEL chemical reactions, efficient and cost-effective evaluation criteria for DNA damage detection are still demanding. Herein, we set standards for evaluating the DNA compatibility of chemistry development at the laboratory level. Based on four typical DNA damage models of three different DEL formats, we evaluated the detection capabilities of four analytical methods, including ultraperformance liquid chromatography (UPLC-MS), electrophoresis, quantitative polymerase chain reaction (qPCR), and Sanger sequencing. This work systematically revealed the scope and capability of different analytical methods in assessing DNA damages caused by chemical transformation. Based on the results, we recommended UPLC-MS and qPCR as efficient methods for DNA barcode integrity analysis in the early-stage development of DNA-compatible chemistry. Meanwhile, we identified that Sanger sequencing was unreliable to assess DNA damage in this application.

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confidence: 99%

Comparative Study of DNA Barcode Integrity Evaluation Approaches in the Early-Stage Development of DNA-Compatible Chemical Transformation

Wang,

Zhao,

Zhang

et al. 2023

ACS Pharmacol. Transl. Sci.

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“…Thus, chemical diversity is one of the most critical characterizations for a library distinguishing itself from others . So far, library construction heavily relies on several widely validated water-compatible reactions like amide formation, nucleophilic substitution, reductive amination and Suzuki coupling . In spite of the abundance of building blocks, the limitation of reaction types could be the Achilles’ Heel for the development of this technology.…”

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confidence: 99%

Construction of Isocytosine Scaffolds via DNA-Compatible Biginelli-like Reaction

Ding¹,

Wu²,

Liu³

et al. 2023

Org. Lett.

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Herein we report a DNA-compatible Biginelli reaction to construct isocytosine scaffolds. This reaction utilizes a one-pot reaction of DNA-conjugated guanidines with aldehydes and methyl cyanoacetates to give isocytosine derivatives, and the method is well compatible with different types of substrates. This is the first report on the synthesis of an isocytosine backbone in the field of DNA-compatible organic synthesis. The successful development of this reaction can widen the chemical space of DELs.

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3.2.1.1 Encoding Using Double-Stranded DNA: A Headpiece-Based DNA Ligation Strategy

Zhou,

Huang,

et al. 2024

DNA-Encoded Libraries

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DNA-encoded chemical libraries (DELs) provide a powerful high-throughput screening platform that is used in both academia and industry. High-quality DELs lay the foundation for reliable DEL selection outcomes, and most pharmaceutical companies would prefer double-stranded DELs (dsDELs) because of their superior stability. Here, we summarize the experimental details for encoding a dsDEL, including the overall encoding strategy, synthetic chemistry of building-block addition, ligation strategies of code elongation, and quality control of the resulting libraries, exemplified with a 320-million-membered benzimidazole dsDEL from GlaxoSmithKline (GSK). We also briefly review the successful selection cases involving the presented libraries to highlight the great potential of dsDELs in drug discovery.

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Advancements in DEL-Compatible Chemical Reactions

Cited by 3 publications

References 82 publications

Comparative Study of DNA Barcode Integrity Evaluation Approaches in the Early-Stage Development of DNA-Compatible Chemical Transformation

Comparative Study of DNA Barcode Integrity Evaluation Approaches in the Early-Stage Development of DNA-Compatible Chemical Transformation

Construction of Isocytosine Scaffolds via DNA-Compatible Biginelli-like Reaction

3.2.1.1 Encoding Using Double-Stranded DNA: A Headpiece-Based DNA Ligation Strategy

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