Photochemical Methods Applied to DNA Encoded Library (DEL) Synthesis

Accounts of Chemical Research, Journal Year: 2023, Volume and Issue: 56(3), P. 385 - 401

Published: Jan. 19, 2023

ConspectusDNA-encoded library technology (DELT) is a new screening modality that allows efficient, cost-effective, and rapid identification of small molecules with potential biological activity. This emerging technique represents an enormous advancement that, in combination other technologies such as high-throughput (HTS), fragment-based lead generation, structure-based drug design, has the to transform how discovery carried out. DELT hybrid which chemically synthesized compounds are linked unique genetic tags (or "barcodes") contain readable information. In this way, millions billions building blocks (BBs) attached on-DNA via split-and-pool synthesis can be evaluated against target single experiment. Polymerase chain reaction (PCR) amplification next-generation sequencing (NGS) analysis sequence oligonucleotides DNA tag used identify those ligands high affinity for target. innovative fusion chemical was conceived 1992 by Brenner Lerner (Proc. Natl. Acad. Sci. 1992, 89, 5381–5383) under accelerated development implementation synthetic techniques protocols compatible DNA. fact, compatibility key parameter increasing chances ligand, central focus been transformations transition robust synthesis. Because sole use amplifiable barcode, its structural integrity during process mandatory. As such, these sensitive, polyfunctional substrates typically requires aqueous solutions within defined pH temperature ranges, considered notable challenge DEL synthesis.Using low-energy visible light driving force promote attractive alternative classical methods, it important well-established tool forging bonds way radical intermediates. Recent advances field photocatalysis extraordinary, powerful research arena still continuous development. Several applications taking advantage mild conditions photoinduced have directed toward synthesis, allowing expansion space available evaluation on-DNA. There no doubts visible-light-driven reactions become one most approaches DELT, given easy they provide construct challenges achieve equal success protocols.Key characteristics photocatalytic include short times efficiency, translate into retention integrity. Account, we describe recent diversification prepared on-DNA, highlighting amenability employed preserving structure molecules. We demonstrate from our group applicability summary table containing all methods reported date demonstrating their aspects scope, applications, compatibilities. With information, practitioners provided compelling reasons developing/choosing applications.

Language: Английский

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Machine-Learning-Based Data Analysis Method for Cell-Based Selection of DNA-Encoded Libraries

ACS Omega, Journal Year: 2023, Volume and Issue: 8(21), P. 19057 - 19071

Published: May 15, 2023

DNA-encoded library (DEL) is a powerful ligand discovery technology that has been widely adopted in the pharmaceutical industry. DEL selections are typically performed with purified protein target immobilized on matrix or solution phase. Recently, DELs have also used to interrogate targets complex biological environment, such as membrane proteins live cells. However, due landscape of cell surface, selection inevitably involves significant nonspecific interactions, and data much noisier than ones proteins, making reliable hit identification highly challenging. Researchers developed several approaches denoise datasets, but it remains unclear whether they suitable for cell-based selections. Here, we report proof-of-principle new machine-learning (ML)-based approach process datasets by using Maximum A Posteriori (MAP) estimation loss function, probabilistic framework can account quantify uncertainties noisy data. We applied dataset, where 7,721,415 compounds was selected against carbonic anhydrase 2 (CA-2) line expressing 12 (CA-12). The extended-connectivity fingerprint (ECFP)-based regression model MAP function able identify true binders structure-activity relationship (SAR) from datasets. In addition, regularized enrichment metric (known enrichment) could be calculated directly without involving specific model, effectively suppressing low-confidence outliers enhancing signal-to-noise ratio. Future applications this method will focus de novo

Language: Английский

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Visible Light-Promoted Divergent Benzoheterocyclization from Aldehydes for DNA-Encoded Chemical Libraries

Organic Letters, Journal Year: 2022, Volume and Issue: 24(17), P. 3291 - 3296

Published: April 25, 2022

Benzoheterocyclics have been widely adopted as drug-like core scaffolds that can be incorporated into DNA-encoded chemical library technology for high-throughput hit discovery. Here, we present a visible light-promoted divergent synthesis of on-DNA benzoheterocycles from aldehydes. Four types DNA-conjugated benzoheterocyclics were obtained under mild conditions with broad substrate scope. A cross scope study, together enzymatic ligation and subsequent diversifications, conducted, demonstrating the feasibility this approach in construction.

Language: Английский

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Selection methods for proximity-dependent enrichment of ligands from DNA-encoded libraries using enzymatic fusion proteins

Chemical Science, Journal Year: 2022, Volume and Issue: 14(2), P. 245 - 250

Published: Nov. 15, 2022

Nanoluciferase or engineered biotin ligase fusions to a protein target allow proximity-induced biotinylation of DNA-linked ligands. The approach benefits ligand enrichment from DNA-encoded chemical libraries (DELs) and live cell selections.

Language: Английский

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Trio-pharmacophore DNA-encoded chemical library for simultaneous selection of fragments and linkers

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: March 17, 2023

Abstract The split-and-pool method has been widely used to synthesize chemical libraries of a large size for early drug discovery, albeit without the possibility meaningful quality control. In contrast, self-assembled DNA-encoded library (DEL) allows us construct an m x n-member by mixing m-member and pre-purified sub-library. Herein, we report trio-pharmacophore DEL (T-DEL) l n members through assembling three validated sub-libraries. middle sub-library is synthesized using DNA-templated synthesis with different reaction mechanisms designed as linkage connecting fragments displayed on flanking two Despite fragments, resulting compounds do not exceed up-to-date standard molecular weight regarding drug-likeness. We demonstrate utility T-DEL in linker optimization known binding against trypsin carbonic anhydrase II de novo selections matrix metalloprotease-2 −9.

Language: Английский

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Advancing small-molecule drug discovery by encoded dual-display technologies

Trends in Pharmacological Sciences, Journal Year: 2023, Volume and Issue: 44(11), P. 817 - 831

Published: Sept. 20, 2023

Language: Английский

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Using DNA-encoded libraries of fragments for hit discovery of challenging therapeutic targets

Expert Opinion on Drug Discovery, Journal Year: 2024, Volume and Issue: 19(6), P. 725 - 740

Published: May 16, 2024

Introduction The effectiveness of Fragment-based drug design (FBDD) for targeting challenging therapeutic targets has been hindered by two factors: the small library size and complexity fragment-to-hit optimization process. DNA-encoded (DEL) technology offers a compelling robust high-throughput selection approach to potentially address these limitations.

Language: Английский

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Assays of DNA-encoded Libraries Against Protein Targets on and Within Living Cells

Royal Society of Chemistry eBooks, Journal Year: 2025, Volume and Issue: unknown, P. 63 - 86

Published: Feb. 21, 2025

Assay platforms available for DNA-encoded chemical libraries (DELs) are largely limited to an in vitro selection assay binding a biochemical pure protein on solid support. Extending DEL assays proteins the cell surface and within live cells offers ability targets that cannot be reconstituted biochemically more physiologically relevant state. Significant challenges exist hinder cellular application of DELs. In this review, we summarise various approaches have been applied date enable against both cells. We discuss benefits limitations these how they address unique assays. explore potential molecular discovery from varying complexity. highlight some molecules discovered successfully with lastly offer outlook future.

Language: Английский

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Discovering Cell‐Targeting Ligands and Cell‐Surface Receptors by Selection of DNA‐Encoded Chemical Libraries against Cancer Cells without Predefined Targets

Angewandte Chemie, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 11, 2025

Abstract Small molecules that can bind to specific cells have broad application in cancer diagnosis and treatment. Screening large chemical libraries against live is an effective strategy for discovering cell‐targeting ligands. The DNA‐encoded library (DEL or DECL) technology has emerged as a robust tool drug discovery been successfully utilized identifying ligands biological targets. However, nearly all DEL selections predefined targets, while target‐agnostic interrogating the entire cell surface remain underexplored. Herein, we systematically optimized cell‐based selection method without A 104.96‐million‐member was selected MDA‐MB‐231 MCF‐7 breast cells, representing high low metastatic properties, respectively, which led identification of cell‐specific small molecules. We further demonstrated applications these photodynamic therapy targeted delivery. Finally, leveraging DNA tag compounds, identified α‐enolase (ENO1) receptor one targeting more aggressive cells. Overall, this work offers efficient approach molecule by using DELs demonstrates be useful identify receptors on

Language: Английский

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Discovering Cell‐Targeting Ligands and Cell‐Surface Receptors by Selection of DNA‐Encoded Chemical Libraries against Cancer Cells without Predefined Targets

Angewandte Chemie International Edition, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 11, 2025

Abstract Small molecules that can bind to specific cells have broad application in cancer diagnosis and treatment. Screening large chemical libraries against live is an effective strategy for discovering cell‐targeting ligands. The DNA‐encoded library (DEL or DECL) technology has emerged as a robust tool drug discovery been successfully utilized identifying ligands biological targets. However, nearly all DEL selections predefined targets, while target‐agnostic interrogating the entire cell surface remain underexplored. Herein, we systematically optimized cell‐based selection method without A 104.96‐million‐member was selected MDA‐MB‐231 MCF‐7 breast cells, representing high low metastatic properties, respectively, which led identification of cell‐specific small molecules. We further demonstrated applications these photodynamic therapy targeted delivery. Finally, leveraging DNA tag compounds, identified α‐enolase (ENO1) receptor one targeting more aggressive cells. Overall, this work offers efficient approach molecule by using DELs demonstrates be useful identify receptors on

Language: Английский

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