Reported Applications of DNA‐Encoded Library Chemistry

Ottl, Johannes

doi:10.1002/9781118832738.ch14

Cited by 8 publications

(6 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…DNA encoded library (DEL) technology allows for facile generation and screening of extremely large numbers of drug-like molecules. − Numerous literature reports illustrate the value of the technology including the discovery of LFA-1, ADAMTS-5, RIP3 kinase, BCATm, InhA, SIRT1–3, Wip1 phosphatase, and sEH inhibitors. DNA encoded libraries (DELs) are commonly synthesized via split-and-pool chemistry, − although a variety of alternative methodologies have been reported. − Regardless of the method of synthesis, the technology results in the generation of complex mixtures of DNA conjugates.…”

Section: Introductionmentioning

confidence: 99%

Simulated Screens of DNA Encoded Libraries: The Potential Influence of Chemical Synthesis Fidelity on Interpretation of Structure–Activity Relationships

Satz

2016

ACS Comb. Sci.

View full text Add to dashboard Cite

Simulated screening of DNA encoded libraries indicates that the presence of truncated byproducts complicates the relationship between library member enrichment and equilibrium association constant (these truncates result from incomplete chemical reactions during library synthesis). Further, simulations indicate that some patterns observed in reported experimental data may result from the presence of truncated byproducts in the library mixture and not structure-activity relationships. Potential experimental methods of minimizing the presence of truncates are assessed via simulation; the relationship between enrichment and equilibrium association constant for libraries of differing purities is investigated. Data aggregation techniques are demonstrated that allow for more accurate analysis of screening results, in particular when the screened library contains significant quantities of truncates.

show abstract

Section: Introductionmentioning

confidence: 99%

Simulated Screens of DNA Encoded Libraries: The Potential Influence of Chemical Synthesis Fidelity on Interpretation of Structure–Activity Relationships

Satz

2016

ACS Comb. Sci.

View full text Add to dashboard Cite

show abstract

“…DNA encoded library technology allows for the rapid generation of extremely large numbers of novel small molecules. The primary use of this technology is to find chemical starting points against pharmaceutically interesting proteins. − In recent years, a number of reports have highlighted the value of the technology, including the discovery of integrin lymphocyte function-associated antigen 1 (LFA-1) antagonists, ADAMTS-5, and RIP3 kinase inhibitors.…”

mentioning

confidence: 99%

DNA Encoded Library Selections and Insights Provided by Computational Simulations

Satz

2015

ACS Chem. Biol.

View full text Add to dashboard Cite

DNA encoded library (DEL) technology allows for rapid generation of extremely large numbers of small molecules and is often used to find novel chemical starting points for pharmaceutically relevant proteins. DEL selection output consists of a list of small-molecule structures and enrichment levels. It is widely presumed that molecules with greater enrichment will have larger equilibrium association constants, and follow-up efforts are triaged accordingly. Herein we describe a simple mathematical model used to simulate DEL selections. Simulations predict that enrichment levels will correlate poorly with equilibrium association constants when selections use high concentrations of protein or lower quality DELs (high variance in final product synthetic yields). A potentially superior technique is demonstrated to qualitatively assess equilibrium association constants directly from sequencing data. This technique requires conducting selections over a range of protein concentrations, so that the influence of synthetic yield can be accounted for.

show abstract

“…For instance, compatible reactions must proceed under conditions that solubilize the DNA substrate, which requires aqueous solutions. Also, reagents must not cause degradation of the DNA oligomer . Additionally, reactions applicable to DEL synthesis must have a broad substrate scope and be operationally simple .…”

Section: Introductionmentioning

confidence: 99%

“…Also, reagents must not cause degradation of the DNA oligomer. 15 Additionally, reactions applicable to DEL synthesis must have a broad substrate scope and be operationally simple. 16 Herein, we report a facile sodium dithionite−mediated nitro reduction in water and subsequent synthesis of benzimidazoles on DNA.…”

Section: ■ Introductionmentioning

confidence: 99%

DNA-Compatible Nitro Reduction and Synthesis of Benzimidazoles

Huang

2017

Bioconjugate Chem.

View full text Add to dashboard Cite

DNA-encoded chemical libraries have emerged as a cost-effective alternative to high-throughput screening (HTS) for hit identification in drug discovery. A key factor for productive DNA-encoded libraries is the chemical diversity of the small molecule moiety attached to an encoding DNA oligomer. The library structure diversity is often limited to DNA-compatible chemical reactions in aqueous media. Herein, we describe a facile process for reducing aryl nitro groups to aryl amines. The new protocol offers simple operation and circumvents the pyrophoric potential of the conventional method (Raney nickel). The reaction is performed in aqueous solution and does not compromise DNA structural integrity. The utility of this method is demonstrated by the versatile synthesis of benzimidazoles on DNA.

show abstract

Reported Applications of DNA‐Encoded Library Chemistry

Cited by 8 publications

References 39 publications

Simulated Screens of DNA Encoded Libraries: The Potential Influence of Chemical Synthesis Fidelity on Interpretation of Structure–Activity Relationships

Simulated Screens of DNA Encoded Libraries: The Potential Influence of Chemical Synthesis Fidelity on Interpretation of Structure–Activity Relationships

DNA Encoded Library Selections and Insights Provided by Computational Simulations

DNA-Compatible Nitro Reduction and Synthesis of Benzimidazoles

Contact Info

Product

Resources

About