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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A Vancomycin-Templated DNA-Encoded Library for Combating Drug-Resistant Bacteria

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(5), P. 3778 - 3794

Published: March 5, 2024

It is an urgent need to tackle the global crisis of multidrug-resistant bacterial infections. We report here innovative strategy for large-scale screening new antibacterial agents using a whole bacteria-based DNA-encoded library (DEL) vancomycin derivatives via peripheral modifications. A binding affinity assay was established select modification fragments in high-affinity compounds. The optimal resynthesized demonstrated excellently enhanced activity against various resistant strains and provided useful structures derivatization. This work presents concept natural product-templated DEL antibiotic discovery through screening, which promotes fight drug-resistant bacteria.

Language: Английский

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Evolution of the Selection Methods of DNA-Encoded Chemical Libraries

Accounts of Chemical Research, Journal Year: 2021, Volume and Issue: 54(17), P. 3491 - 3503

Published: Aug. 24, 2021

ConspectusIn the past two decades, a DNA-encoded chemical library (DEL or DECL) has emerged and become major technology platform for ligand discovery in drug as well biology research. Although based on simple concept, i.e., encoding each compound with unique DNA tag combinatorial library, DEL been proven to be powerful tool interrogating biological targets by accessing vast space at fraction of cost traditional high-throughput screening (HTS). Moreover, recent technological advances rapid developments DEL-compatible reactions have greatly enhanced diversity DELs. Today, DELs adopted nearly all pharmaceutical companies are also gaining momentum academia. However, this field is heavily biased toward synthesis, an underexplored aspect research selection methods. Generally, considered massive binding assay conducted over immobilized protein identify physical binders using typical bind–wash–elute procedure. In years, we other groups developed new approaches that can perform selections solution phase, which enabled against complex beyond purified proteins. On one hand, these methods significantly widened target scope DELs; they functional potentially phenotypic assays binding. An overview provided Account.Our laboratory DNA-programmed affinity labeling (DPAL) main strategy develop DPAL DNA-templated synthesis; known guide binding, able specifically establish stable linkage between ligand. The target-ligand conjugates serves programmable handle characterization hit decoding case selections. takes advantage fast reaction kinetics photo-cross-linking achieve high specificity fidelity, especially dynamic libraries (DEDLs). not only buffer cell lysates but systems, such large complexes live cells. employed applications, site-specific labeling, detection, profiling, identification. Account, describe methods, highlight their underlying principles, conclude perspectives development technology.

Language: Английский

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A Small Molecule Selected from a DNA‐Encoded Library of Natural Products That Binds to TNF‐α and Attenuates Inflammation In Vivo

Advanced Science, Journal Year: 2022, Volume and Issue: 9(21)

Published: May 21, 2022

Tumor necrosis factor α (TNF-α) inhibitors have shown great success in the treatment of autoimmune diseases. However, to date, approved drugs targeting TNF-α are restricted biological macromolecules, largely due difficulties using small molecules for pharmaceutical intervention protein-protein interactions. Herein power a natural product-enriched DNA-encoded library (nDEL) is exploited identify that interfere with interaction between and cognate receptor. Initially, select capable binding , "late-stage" DNA modification method applied construct an nDEL consisted 400 sterically diverse products pharmaceutically active chemicals. Several products, including kaempferol, identified not only show direct TNF-α, but also lead blockage TNF-α/TNFR1 interaction. Significantly, kaempferol attenuates signaling cells reduces 12-O-tetradecanoylphorbol-13-acetateinduced ear inflammation mice. Structure-activity-relationship analyses demonstrate importance substitution groups at C-3, C-7, C-4' kaempferol. The hit, represents novel chemical scaffold specifically recognizing blocking its signal transduction, promising starting point development molecule inhibitor use clinical setting.

Language: Английский

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The Insulin Receptor: An Important Target for the Development of Novel Medicines and Pesticides

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(14), P. 7793 - 7793

Published: July 14, 2022

The insulin receptor (IR) is a transmembrane protein that activated by ligands in signaling pathways. IR has been considered as novel therapeutic target for clinical intervention, considering the overexpression of its and A-isoform multiple cancers, Alzheimer's disease, Type 2 diabetes mellitus humans. Meanwhile, it may also serve potential pest management due to physiological influences insects. In this review, we provide an overview structural molecular biology IR, functions IRs humans insects, nonpeptide small molecule modulators regulating mechanisms IR. Xenobiotic compounds corresponding insecticidal chemicals functioning on are discussed. This review expected useful information better understanding human IR-related diseases, well facilitate development small-molecule activators inhibitors use medicines or pesticides.

Language: Английский

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Palladium-catalyzed one-pot phosphorylation of phenols mediated by sulfuryl fluoride

Chemical Communications, Journal Year: 2021, Volume and Issue: 57(37), P. 4588 - 4591

Published: Jan. 1, 2021

A one-pot palladium-catalyzed procedure for the synthesis of aryl phosphonates, phosphinates and phosphine oxides from phenols mediated by sulfuryl fluoride.

Language: Английский

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Click Chemistry in Natural Product Modification

Frontiers in Chemistry, Journal Year: 2021, Volume and Issue: 9

Published: Nov. 17, 2021

Click chemistry is perhaps the most powerful synthetic toolbox that can efficiently access molecular diversity and unique functions of complex natural products up to now. It enables ready synthesis diverse sets product derivatives either for optimization their drawbacks or construction product-like drug screening libraries. This paper showcases state-of-the-art development click in modification summarizes pharmacological activities active as well mechanism action. The aim this gain a deep understanding fruitful achievements provide perspectives, trends, directions regarding further research medicinal chemistry.

Language: Английский

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Agonist Discovery for Membrane Proteins on Live Cells by Using DNA-encoded Libraries

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(35), P. 24638 - 24653

Published: Aug. 22, 2024

Identifying biologically active ligands for membrane proteins is an important task in chemical biology. We report approach to directly identify small molecule agonists against by selecting DNA-encoded libraries (DELs) on live cells. This method connects extracellular ligand binding with intracellular biochemical transformation, thereby biasing the selection toward agonist identification. have demonstrated methodology three proteins: epidermal growth factor receptor (EGFR), thrombopoietin (TPOR), and insulin (INSR). A ∼30 million a 1.033 billion-compound DEL were selected these targets, novel subnanomolar affinity low micromolar cellular activities been discovered. The INSR activated possibly allosteric site, exhibited clear synergistic effects insulin, downstream signaling pathways. Notably, did not activate insulin-like 1 (IGF-1R), highly homologous whose activation may lead tumor progression. Collectively, this work has developed "functional" selections cell surface provide widely applicable discovery proteins.

Language: Английский

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The maturation of DNA encoded libraries: opportunities for new users

Future Medicinal Chemistry, Journal Year: 2020, Volume and Issue: 13(2), P. 173 - 191

Published: Dec. 4, 2020

DNA-encoded combinatorial libraries (DECLs) represent an exciting new technology for high-throughput screening, significantly increasing its capacity and cost–effectiveness. Historically, DECLs have been the domain of specialized academic groups industry; however, there has recently a shift toward more drug discovery centers institutes adopting this technology. Key to development simplification, characterization standardization various DECL subprotocols, such as library design, affinity screening data analysis hits. This review examines feasibility implementing first-time user, particularly in academia, exploring some important considerations this, outlines applications that academia could contribute field.

Language: Английский

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Recent Advances on the Selection Methods of DNA‐Encoded Libraries

ChemBioChem, Journal Year: 2021, Volume and Issue: 22(14), P. 2384 - 2397

Published: April 23, 2021

DNA-encoded libraries (DEL) have come of age and become a major technology platform for ligand discovery in both academia the pharmaceutical industry. Technological maturation past two decades recent explosive developments DEL-compatible chemistries greatly improved chemical diversity DELs fueled its applications drug discovery. A relatively less-covered aspect is selection method. Typically, DEL considered as binding assay conducted with purified protein targets immobilized on matrix, binders are separated from non-binding background via physical washes. However, innovations methods not only expanded target scope DELs, but also revealed potential powerful tool exploring fundamental biology. In this Review, we first cover "classic" proteins solid phase, then discuss strategies to realize selections solution phase. Finally, focus emerging approaches interrogate complex biological targets.

Language: Английский

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