Chemical Evolution of Natural Product Structure

Journal of the American Chemical Society, Journal Year: 2022, Volume and Issue: 144(8), P. 3314 - 3329

Published: Feb. 21, 2022

Natural products are the result of Nature's exploration biologically relevant chemical space through evolution and an invaluable source bioactive small molecules for biology medicinal chemistry. Novel concepts discovery new compound classes based on natural product structure may enable wider space. The pseudo-natural concept merges relevance with efficient by means fragment-based development to inspire matter de novo combination fragments in unprecedented arrangements. novel scaffolds retain biological but not obtainable known biosynthetic pathways which can lead chemotypes that have unexpected or bioactivities. Herein, we cover workflow design development, highlight recent examples, discuss a cheminformatic analysis significant portion active synthetic compounds were found be products. We compare as human-made equivalent, i.e. structure.

Language: Английский

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Small-molecule discovery through DNA-encoded libraries

Nature Reviews Drug Discovery, Journal Year: 2023, Volume and Issue: 22(9), P. 699 - 722

Published: June 16, 2023

Language: Английский

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Navigating large chemical spaces in early-phase drug discovery

Current Opinion in Structural Biology, Journal Year: 2023, Volume and Issue: 80, P. 102578 - 102578

Published: April 4, 2023

The size of actionable chemical spaces is surging, owing to a variety novel techniques, both computational and experimental. As consequence, molecular matter now at our fingertips that cannot should not be neglected in early-phase drug discovery. Huge, combinatorial, make-on-demand with high probability synthetic success rise exponentially content, generative machine learning models go hand synthesis prediction, DNA-encoded libraries offer new ways hit structure These technologies enable search for much broader deeper manner less effort fewer financial resources. transformational developments require cheminformatics approaches make huge searchable analyzable low resources, as little energy consumption possible. Substantial progress has been made the past years respect computation well organic synthesis. First examples bioactive compounds resulting from successful use these demonstrate their power contribute tomorrow's discovery programs. This article gives compact overview state-of-the-art.

Language: Английский

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Protein-templated ligand discovery via the selection of DNA-encoded dynamic libraries

Nature Chemistry, Journal Year: 2024, Volume and Issue: 16(4), P. 543 - 555

Published: Feb. 7, 2024

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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Converting Double-Stranded DNA-Encoded Libraries (DELs) to Single-Stranded Libraries for More Versatile Selections

ACS Omega, Journal Year: 2022, Volume and Issue: 7(13), P. 11491 - 11500

Published: March 24, 2022

DNA-encoded library (DEL) is an efficient high-throughput screening technology platform in drug discovery and also gaining momentum academic research. Today, the majority of DELs are assembled encoded with double-stranded DNA tags (dsDELs) has been selected against numerous biological targets; however, dsDELs not amendable to some recently developed selection methods, such as cross-linking-based immobilized targets live-cell-based selections, which require single-stranded DNAs (ssDELs). Herein, we present a simple method convert ssDELs using exonuclease digestion without redesign resynthesis. We show that could be efficiently converted used for affinity-based selections either purified proteins or on live cells.

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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Drug discovery technologies–Current and future trends

Elsevier eBooks, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

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High-Throughput Screening of Stapled Helical Peptides in Drug Discovery

Journal of Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 66(1), P. 95 - 106

Published: Dec. 29, 2022

Therapeutic peptides have revolutionized treatment for a number of human diseases. In particular, the past two decades witnessed rapid progress stapled helical in drug discovery. Stapled are chemically modified and constrained their bioactive α-helical conformation. Compared to unstabilized linear peptides, exhibit superior binding affinity selectivity, enhanced membrane permeability, improved metabolic stability, presenting exciting promise targeting otherwise challenging protein–protein interfaces. this Perspective, we summarize recent applications high-throughput screening technologies identification potent with optimized properties. We expect provide broad reference accelerate development as next generation therapeutic various

Language: Английский

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Identification of isoform/domain-selective fragments from the selection of DNA-encoded dynamic library

Bioorganic & Medicinal Chemistry, Journal Year: 2021, Volume and Issue: 45, P. 116328 - 116328

Published: July 25, 2021

Language: Английский

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