What is a “DNA-Compatible” Reaction?

Malone, Marie L.; Paegel, Brian M.

doi:10.1021/acscombsci.5b00198

Cited by 182 publications

(232 citation statements)

References 48 publications

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“…Notably, the following considerations have to be confronted: 1) Due to the high functionalization of DNA, [17,43] on-DNA reactions are typically carried out in aqueous media (with > 20% water as co-solvent) at extremely high dilution (0.1 × 10 -3 −1 × 10 −3 m for DELs vs 0.1-1 m for conventional chemical reactions) under mild reaction conditions (pH 4-14 and 25-90 °C); 2) the reactions must be robust and amenable to a wide scope of substrates and coupling partners, especially for those containing heterocycles, since heterocycles such as indole, pyridine, etc., are privileged structures in small molecule drugs. Notably, the following considerations have to be confronted: 1) Due to the high functionalization of DNA, [17,43] on-DNA reactions are typically carried out in aqueous media (with > 20% water as co-solvent) at extremely high dilution (0.1 × 10 -3 −1 × 10 −3 m for DELs vs 0.1-1 m for conventional chemical reactions) under mild reaction conditions (pH 4-14 and 25-90 °C); 2) the reactions must be robust and amenable to a wide scope of substrates and coupling partners, especially for those containing heterocycles, since heterocycles such as indole, pyridine, etc., are privileged structures in small molecule drugs.…”

Section: Introductionmentioning

confidence: 99%

DNA‐Encoded Libraries: Aryl Fluorosulfonates as Versatile Electrophiles Enabling Facile On‐DNA Suzuki, Sonogashira, and Buchwald Reactions

Wang

et al. 2019

Advanced Science

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are encoded by unique DNA sequences as identification "barcodes," and are assembled combinatorial using split-andpool strategy or alternative procedures via DNA-compatible reactions. [7][8][9] DELs comprising millions or even billions of DNA-tagged druglike molecules can be effectively synthesized via this technology and screened against various protein targets of interest in a single pooled assay. In a typical affinity-based selection experiment, when non-and low-affinity binders are washed away, the DNA tag of the remaining compounds can be amplified using polymerase chain reaction and the relative frequency of the remaining compounds before and after selection is determined by counting the number of DNA tags in high-throughput DNA sequencing experiments. [10,11] To date, a large number of high-quality hits have been identified by the DEL technology for various therapeutically relevant targets, such as kinases, [12] phosphatases, [13] and G-protein coupled receptors. [14] Several drug candidates derived from their corresponding DEL hits, such as soluble epoxide hydrolase inhibitor GSK2256294, and death domain receptor-associated adaptor kinase RIP1 inhibitor GSK2982772 have progressed to latestage clinical development, [15,16] further emphasizing DEL as a powerful technology for small molecular drug discovery.Despite these successes, the great potential of DEL technology in drug discovery has not yet been fully realized. One of the most fundamental challenges is the synthesis of high-quality libraries with more structural diversity, which in turn depends on the development of new and robust DNA-compatible reactions that allow more flexibility in DEL's design and synthesis. Among various DNA-compatible reactions developed in recent years, transition-metal-promoted reactions such as Suzuki-Miyaura coupling, [17][18][19][20][21][22][23] Sonogashira coupling, and Buchwald-Hartwig amination using DNA-conjugated aryl halides as electrophiles have been elegantly developed (Figure 1), [24][25][26] and some of them have been developed for DEL synthesis. However, the environmental toxicity and high costs of aryl halides have hindered their large-scale applications in industry. Thus, much attention has been paid to phenol-derived electrophiles recently, [27] which, as compared to aryl halides, offer a more sustainable starting material because most of them are readily available from biomass. [28] In addition, phenol modules are also important components of natural products (NPs), bioactive molecules, and pharmaceutical drugs. Coupling reactions with Using (hetero)aryl fluorosulfonates as versatile electrophiles, facile on-DNA cross-coupling reactions of Suzuki, Sonogashira, and Buchwald are reported here. Notably, all of these reactions show excellent functional group tolerance, mild reaction conditions (relative low temperature and open to air), rich heterocyclic coupling partners, and more importantly, DNA-compatibility. Thus, these new reactions based on efficient formation of C(sp 2 )-C(sp 2 ), C(sp 2 )-C(sp), and C(s...

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Section: Introductionmentioning

confidence: 99%

DNA‐Encoded Libraries: Aryl Fluorosulfonates as Versatile Electrophiles Enabling Facile On‐DNA Suzuki, Sonogashira, and Buchwald Reactions

Wang

et al. 2019

Advanced Science

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“…7,15−17 Using DNA, it is possible to prepare large and structurally complex compound collections, encoding myriad structures and thereby accessing diverse chemical space. 18−20 Importantly, DEL screening output can be analyzed by highly parallel next-generation DNA sequencing (NGS), 17,21 revealing hit homology 22−24 and guiding selection of structural families for lower throughput synthesis and validation. Adaptation of DEL to solid-phase libraries 25 provides additional certainty to hit prioritization via reproducibility.…”

Section: Introductionmentioning

confidence: 99%

Poisson Statistics of Combinatorial Library Sampling Predict False Discovery Rates of Screening

MacConnell

Paegel

2017

ACS Comb. Sci.

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Microfluidic droplet-based screening of DNA-encoded one-bead-one-compound combinatorial libraries is a miniaturized, potentially widely distributable approach to small molecule discovery. In these screens, a microfluidic circuit distributes library beads into droplets of activity assay reagent, photochemically cleaves the compound from the bead, then incubates and sorts the droplets based on assay result for subsequent DNA sequencing-based hit compound structure elucidation. Pilot experimental studies revealed that Poisson statistics describe nearly all aspects of such screens, prompting the development of simulations to understand system behavior. Monte Carlo screening simulation data showed that increasing mean library sampling (ε), mean droplet occupancy, or library hit rate all increase the false discovery rate (FDR). Compounds identified as hits on k > 1 beads (the replicate k class) were much more likely to be authentic hits than singletons (k = 1), in agreement with previous findings. Here, we explain this observation by deriving an equation for authenticity, which reduces to the product of a library sampling bias term (exponential in k) and a sampling saturation term (exponential in ε) setting a threshold that the k-dependent bias must overcome. The equation thus quantitatively describes why each hit structure’s FDR is based on its k class, and further predicts the feasibility of intentionally populating droplets with multiple library beads, assaying the micromixtures for function, and identifying the active members by statistical deconvolution.

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“…A diverse set of reactions have been successfully validated in a DNA-templated manner 36, 38 and a broader toolbox of DNA-compatible chemistry is steadily growing. 8, 39, 40 Our group has applied this concept to create libraries of DNA-templated small molecules 6 , in which the DNA tags not only function as barcodes, but also as templates that orchestrate the synthesis of each library member.…”

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confidence: 99%

Second-generation DNA-templated macrocycle libraries for the discovery of bioactive small molecules

et al. 2018

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DNA-encoded libraries have emerged as a widely used resource for discovery of bioactive small molecules and offer substantial advantages compared to conventional small-molecule libraries. Here we developed and streamlined multiple fundamental aspects of DNA-encoded and DNA-templated library synthesis methodology, including computational identification and experimental validation of a 20×20×20×80 set of orthogonal codons, chemical and computational tools for enhancing the structural diversity and drug-likeness of library members, a highly efficient polymerase-mediated template library assembly strategy, and library isolation and purification methods. We integrated these improved methods to produce a second-generation DNA-templated library of 256,000 small-molecule macrocycles with improved drug-like physical properties. In vitro selection of this library for insulin-degrading enzyme (IDE) affinity resulted in novel IDE inhibitors including one of unusual potency and novel macrocycle stereochemistry (IC50 = 40 nM). Collectively, these developments enable DNA-templated small-molecule libraries to serve as more powerful, accessible, streamlined, and cost-effective tools for bioactive small-molecule discovery.

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What is a “DNA-Compatible” Reaction?

Cited by 182 publications

References 48 publications

DNA‐Encoded Libraries: Aryl Fluorosulfonates as Versatile Electrophiles Enabling Facile On‐DNA Suzuki, Sonogashira, and Buchwald Reactions

DNA‐Encoded Libraries: Aryl Fluorosulfonates as Versatile Electrophiles Enabling Facile On‐DNA Suzuki, Sonogashira, and Buchwald Reactions

Poisson Statistics of Combinatorial Library Sampling Predict False Discovery Rates of Screening

Second-generation DNA-templated macrocycle libraries for the discovery of bioactive small molecules

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