On-DNA hit validation methodologies for ligands identified from DNA-encoded chemical libraries

Prati, Luca; Bigatti, Martina; Donckèle, Etienne J.; Neri, Dario; Samain, Florent

doi:10.1016/j.bbrc.2020.04.030

Cited by 22 publications

(21 citation statements)

References 27 publications

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“…The compounds displayed a weak interaction with streptavidin, with dissociation constants Kd = 37 ± 2 and 42 ± 3 × 10 −6 m , respectively, which were measured by a small molecule ELISA procedure, recently described by our group. [ 17 ] Selections were also performed against human carbonic anhydrase IX, a tumor‐associated antigen and a marker of hypoxia. [ 18 ] As expected, aromatic sulfonamides derivatives were found to be preferentially enriched (with enrichment factors (EF) up to 969‐fold), as revealed by the lines at coordinates A94, A250, and B575 of the fingerprints in 3D display mode (Figure 2c).…”

Section: Resultsmentioning

confidence: 99%

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A Single‐Stranded DNA‐Encoded Chemical Library Based on a Stereoisomeric Scaffold Enables Ligand Discovery by Modular Assembly of Building Blocks

et al. 2020

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A versatile and Lipinski-compliant DNA-encoded library (DEL), comprising 366 600 glutamic acid derivatives coupled to oligonucleotides serving as amplifiable identification barcodes is designed, constructed, and characterized. The GB-DEL library, constructed in single-stranded DNA format, allows de novo identification of specific binders against several pharmaceutically relevant proteins. Moreover, hybridization of the single-stranded DEL with a set of known protein ligands of low to medium affinity coupled to a complementary DNA strand results in self-assembled selectable chemical structures, leading to the identification of affinity-matured compounds.

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Section: Resultsmentioning

confidence: 99%

“…Error bars on the curve indicate standard deviation of the three measurements. The Kd values ± standard error for compound [16][17][18][19] are given next to the chemical structures.…”

Section: Supporting Informationmentioning

confidence: 99%

A Single‐Stranded DNA‐Encoded Chemical Library Based on a Stereoisomeric Scaffold Enables Ligand Discovery by Modular Assembly of Building Blocks

et al. 2020

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“…However, it is also recognized that byproduct hits could contribute to the perceived false-positive results arising from these approaches. Several studies also described assessment methods for DNA–conjugate using ELISA and SPR, − which are considered a more straightforward approach for validating DEL-derived hits, but cannot differentiate different components from the DNA–conjugate. Deciphering the complication of combinatorial synthesis has been a long-standing challenge of data deconvolution in the DEL selection process.…”

Section: Discussionmentioning

confidence: 99%

Triaging of DNA-Encoded Library Selection Results by High-Throughput Resynthesis of DNA–Conjugate and Affinity Selection Mass Spectrometry

Ding

Chen

et al. 2021

Bioconjugate Chem.

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DNA encoded library (DEL) technology allows for rapid identification of novel small-molecule ligands and thus enables early-stage drug discovery. DEL technology is well-established, numerous cases of discovered hit molecules have been published, and the technology is widely employed throughout the pharmaceutical industry. Nonetheless, DEL selection results can be difficult to interpret, as library member enrichment may derive from not only desired products, but also DNA-conjugated byproducts and starting materials. Note that DELs are generally produced using split-and-pool combinatorial chemistry, and DNAconjugated byproducts and starting materials cannot be removed from the library mixture. Herein, we describe a method for highthroughput parallel resynthesis of DNA-conjugated molecules such that byproducts, starting materials, and desired products are produced in a single pot, using the same chemical reactions and reagents as during library production. The low-complexity mixtures of DNA−conjugate are then assessed for protein binding by affinity selection mass spectrometry and the molecular weights of the binding ligands ascertained. This workflow is demonstrated to be a practical tool to triage and validate potential hits from DEL selection data.

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“… 32 For CAII selections, since monovalent SABA has an 0.6 μM affinity for CAII, this means that avidity was greatly helping to retrieve the SABA moiety. 50 …”

Section: Resultsmentioning

confidence: 99%

Universal encoding of next generation DNA-encoded chemical libraries

et al. 2022

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On-DNA hit validation methodologies for ligands identified from DNA-encoded chemical libraries

Cited by 22 publications

References 27 publications

A Single‐Stranded DNA‐Encoded Chemical Library Based on a Stereoisomeric Scaffold Enables Ligand Discovery by Modular Assembly of Building Blocks

A Single‐Stranded DNA‐Encoded Chemical Library Based on a Stereoisomeric Scaffold Enables Ligand Discovery by Modular Assembly of Building Blocks

Triaging of DNA-Encoded Library Selection Results by High-Throughput Resynthesis of DNA–Conjugate and Affinity Selection Mass Spectrometry

Universal encoding of next generation DNA-encoded chemical libraries

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