Synthesis of Diacylhydrazine Derivatives Based on Tetrazole-Focused DNA-Encoded Library

Organic Letters, Journal Year: 2024, Volume and Issue: 26(5), P. 1094 - 1099

Published: Jan. 26, 2024

Utilizing already existing DNA-encoded libraries (DELs) for the generation of a distinct DEL represents an expedited strategy expanding chemical space. Herein, we leverage unique photoreactivity tetrazoles to synthesize diacylhydrazines on DNA. Widely available carboxylic acids serving as building blocks were employed under mild photomediated reaction conditions, affording diverse DNA-conjugated diacylhydrazines. This methodology also demonstrates robustness in DEL-compatible synthesis and facilitates preparation oligonucleotide-based probes.

Language: Английский

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DNA-compatible one-pot synthesis of multi-substituted dihydrofuran via pyridinium ylide-mediated cyclization

Organic & Biomolecular Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Synthesis of chemically diverse heterocyclic scaffolds in DNA-encoded libraries is highly demanded. We herein reported a convenient one-pot multi-component on-DNA synthetic strategy to afford multi-substituted 2,3-dihydrofuran via pyridinium ylide-mediated cyclization. This reaction exhibited modest excellent conversions for broad range DNA-conjugated aldehydes, β-ketonitriles and salts under mild conditions. Furthermore, the compatibility this with DEL construction was verified by enzymatic DNA ligation, PCR amplification mock library synthesis.

Language: Английский

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DNA-encoded Library Machine Learning Applications

Royal Society of Chemistry eBooks, Journal Year: 2025, Volume and Issue: unknown, P. 17 - 40

Published: Feb. 21, 2025

Machine learning (ML) has begun to realize its promise in many domains the last several years. While small molecule drug discovery lagged comparison other areas, developments computing capabilities, data generation, and algorithms have enabled significant progress prediction. DNA-encoded libraries (DELs) represent an efficient way generate quantity of required for effective model building, providing a mechanism protein-target specific prediction with economics that permit individual organizations operate. DEL-based machine (DEL-ML) been demonstrated work variety targets continues expand usage industry approaches reported. With this initial success, number challenges considerations faced by DEL-ML practitioner identified including denoising DEL data, choice ML algorithm, hyperparameters representations, need relevant metrics assessment, particularly given high resource time costs testing predictions. In order fully potential DEL-ML, key improvements infrastructure broad availability are needed.

Language: Английский

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Advances in next-generation sequencing (NGS) applications in drug discovery and development

Expert Opinion on Drug Discovery, Journal Year: 2025, Volume and Issue: unknown

Published: March 18, 2025

Drug discovery is a complex and multifaceted process driven by scientific innovation advanced technologies. Next-Generation Sequencing (NGS) platforms, encompassing both short-read long-read technologies, have revolutionized the field enabling high-throughput cost-effective analysis of DNA RNA molecules. Continuous advancements in NGS-based technologies enabled their seamless integration across preclinical clinical workflows drug discovery, early-stage target identification, candidate selection, genetically stratified trials, pharmacogenetic studies. This review provides an overview current potential applications development process, including roles novel screening, medication The based on literature retrieval from PubMed Web Science databases between 2018 2024. As advance rapidly, NGS enhances accuracy generates vast datasets. These datasets are extensively integrated with other heterogeneous data systems biology mined using machine learning to extract significant insights, thereby driving progress discovery.

Language: Английский

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Synthesis of Functionalized Triazoles on DNA via Azide-Acetonitrile “Click” Reaction

Organic Letters, Journal Year: 2023, Volume and Issue: 25(46), P. 8326 - 8331

Published: Nov. 9, 2023

Triazoles are privileged structural motifs that embedded in a number of molecules with interesting biological activities. In this work, we developed practical and general synthetic strategy to construct medicinally important 5-amino-1,2,3-triazole moiety on DNA by coupling DNA-conjugated azides monosubstituted acetonitriles via azide-acetonitrile "click" reaction. Under mild reaction conditions, displayed broad substrate scope. Most substrates gave moderate-to-excellent conversions. Thus, DNA-compatible could be employed DNA-encoded library (DEL) construction potentially expand the chemical space libraries.

Language: Английский

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Synthesis of Thiohydantoin Scaffolds on DNA for Focused DNA-Encoded Library Construction

Organic Letters, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 3, 2024

Thiohydantoin represents a significant class of biologically active privileged heterocyclic scaffolds. Herein, we present convenient and robust DNA-compatible method for constructing thiohydantoin-focused DNA-encoded library. This reaction can be applied to wide variety isothiocyanate partners, arylamine feedstocks, diverse α-amine acid derivatives, exhibiting excellent conversions, high functional group tolerance, preservation DNA tag integrity. Our allows easy access valuable three-cycle

Language: Английский

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FSO₂N₃-Mediated On-DNA Diazo-Transfer Chemistry

ACS Medicinal Chemistry Letters, Journal Year: 2024, Volume and Issue: 15(9), P. 1591 - 1597

Published: Aug. 23, 2024

DNA-encoded library (DEL) is a powerful hit selection technique in both basic science and innovative drug discovery. In this study, we report robust straightforward DNA-compatible diazo-transfer reaction utilizing FSO

Language: Английский

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DNA‐Compatible Nitriles Hydrolysis for Late‐Stage Functionalization of DNA‐Encoded Libraries

Asian Journal of Organic Chemistry, Journal Year: 2024, Volume and Issue: 13(11)

Published: Aug. 26, 2024

Abstract Primary amides play a crucial role in organic and pharmaceutical synthesis. Herein, we present rapid convenient method for transforming diverse DNA‐conjugated nitriles into primary utilizing hydrogen peroxide potassium carbonate. The substrate scope DEL compatibility of this reaction were thoroughly investigated, revealing wide range substrates with moderate‐to‐excellent conversion. This on‐DNA transformation holds significant promise constructing DNA‐encoded libraries (DELs) enabling late‐stage functionalization to expand chemical diversity. Our approach not only highlights the versatility but also underscores its potential broad applications

Language: Английский

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Challenges and Prospects of DNA-Encoded Library Data Interpretation

Chemical Reviews, Journal Year: 2024, Volume and Issue: 124(22), P. 12551 - 12572

Published: Nov. 7, 2024

DNA-encoded library (DEL) technology is a powerful platform for the efficient identification of novel chemical matter in early drug discovery process enabled by parallel screening vast libraries encoded small molecules through affinity selection and deep sequencing. While DEL selections provide rich data sets computational discovery, underlying technical factors influencing remain incompletely understood. This review systematically examines key parameters affecting information their impact on hit triaging machine learning integration. The need rigorous handling interpretation emphasized, with standardized methods being critical success DEL-based approaches. Major challenges include relationship between sequence counts binding affinities, frequent hitters, influence such as inhomogeneous composition, DNA damage, linkers modes. Experimental artifacts, those caused protein immobilization matrix effects, further complicate interpretation. Recent advancements using to denoise predict candidates are highlighted. offers practical guidance adopting best practices integrating robust methodologies, comprehensive analysis, tools improve accuracy efficacy DEL-driven discovery.

Language: Английский

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The Furan–Thiol–Amine Reaction Facilitates DNA-Compatible Thiopyrrole-Grafted Macrocyclization and Late-Stage Amine Transformation

Organic Letters, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 25, 2024

We here report an efficient DNA-compatible furan-thiol-amine reaction for macrocyclization and late-stage amine transformation. This reaction, conducted under mild conditions, enables the facile cyclization of DNA-conjugated linear peptides into thiopyrrole-grafted macrocycles regardless ring size or side-chain modification with good to excellent conversion yields. Additionally, this strategy was employed transformation terminal amines, serving as critical intermediates in construction DNA-encoded peptide libraries. Diverse amines were successfully converted their corresponding thiopyrrole scaffolds, thereby expanding structural diversity that can be achieved within

Language: Английский

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