A data science roadmap for open science organizations engaged in early-stage drug discovery

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: July 5, 2024

The Structural Genomics Consortium is an international open science research organization with a focus on accelerating early-stage drug discovery, namely hit discovery and optimization. We, as many others, believe that artificial intelligence (AI) poised to be main accelerator in the field. question then how best benefit from recent advances AI generate, format disseminate data enable future breakthroughs AI-guided discovery. We present here recommendations of working group composed experts both public private sectors. Robust management requires precise ontologies standardized vocabulary while centralized database architecture across laboratories facilitates integration into high-value datasets. Lab automation opening electronic lab notebooks mining push boundaries sharing modeling. Important considerations for building robust machine-learning models include transparent reproducible processing, choosing most relevant representation, defining right training test sets, estimating prediction uncertainty. Beyond data-sharing, cloud-based computing can harnessed build models. vectors acceleration chemical probe will (1) real-time experimental generation modeling workflows within design-make-test-analyze (DMTA) cycles openly, at scale (2) adoption mindset where scientists experimentalists work unified team, incorporated design.

Language: Английский

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Bias translation: The final frontier?

British Journal of Pharmacology, Journal Year: 2024, Volume and Issue: 181(9), P. 1345 - 1360

Published: Feb. 29, 2024

Biased signalling is a natural result of GPCR allosteric function and should be expected from any all synthetic agonists. Therefore, it may encountered in agonist discovery projects must considered as beneficial (or possible detrimental) feature new candidate molecules. While bias detected easily, the synoptic nature makes translation simple vitro to complex vivo systems problematic. The practical outcome this difficulty predicting therapeutic value biased due failure identified agonism. This discussed review well some ways forward improve process better exploit powerful pharmacologic mechanism.

Language: Английский

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Split Proteins and Reassembly Modules for Biological Applications

ChemBioChem, Journal Year: 2024, Volume and Issue: 25(10)

Published: March 26, 2024

Abstract Split systems, modular entities enabling controlled biological processes, have become instrumental in research. This review highlights their utility across applications like gene regulation, protein interaction identification, and biosensor development. Covering significant progress over the last decade, it revisits traditional split proteins such as GFP, luciferase, inteins, explores advancements technologies Cas base editors. We also examine reassembly modules diverse fields, from regulation to therapeutic innovation. offers a comprehensive perspective on recent evolution of systems

Language: Английский

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DNA-Encoded Library Technology─A Catalyst for Covalent Ligand Discovery

ACS Chemical Biology, Journal Year: 2024, Volume and Issue: 19(4), P. 802 - 808

Published: March 25, 2024

The identification of novel covalent ligands for therapeutic purposes has long depended on serendipity, with dedicated hit finding techniques emerging only in the early 2000s. Advances chemoproteomics have enabled robust characterization putative drugs to derisk unique liabilities associated molecules, leading a renewed interest this targeting modality. DNA-encoded library (DEL) technology similarly emerged over past two decades as highly efficient method identify new chemical equity toward protein targets interest. A number commercial and academic groups reported methods DEL synthesis identification; however, it is evident that there still much be done fully realize power ligand discovery. This perspective will explore current approaches reflect next steps advance field.

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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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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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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Affinity-based DEL Selections with Different Target Types: Overview and Achievements

Royal Society of Chemistry eBooks, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 16

Published: Feb. 21, 2025

DNA-encoded library (DEL) selection is typically an affinity-based process that encompasses the incubation of DELs with a target, separation compounds bind target from those do not bind, amplification and sequencing DNA barcodes, decoding to reveal chemical structures binders. DEL technology has had notable impact in drug discovery various projects progressing into different stages development clinical trials. methodology allows for ultra-high throughput screening, permitting exploration broad diversity rapid identification hits exhibit desired effects specific targets. have been successfully employed small molecules targeting variety pharmaceutical targets, including proteins nucleic acids. This approach expedited tool probe biological processes hit progressed candidates, thereby facilitating process. In this chapter, we provide overview affinity strategies achievements selections on types.

Language: Английский

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Solid-phase DNA-encoded Library Technology

Royal Society of Chemistry eBooks, Journal Year: 2025, Volume and Issue: unknown, P. 41 - 62

Published: Feb. 21, 2025

Solid-phase DNA-encoded library (DEL) technology introduces advanced activity-based screening capabilities by virtue of its “one-bead-one-compound” (OBOC) format. In this review, we first describe the design and construction so-called “OBOC-DELs.” We then explore engineering a microfluidic platform that integrates automates high-throughput bead-based screening, highlighting examples fluorescence-based functional assay development miniaturization to droplets. Additionally, detail statistical framework OBOC-DEL experimental data interpretation. Finally, summarize numerous applications have spawned since technology’s inception, including biochemical activity, dose-response, cellular competition binding affinity, pharmacokinetic properties. Looking forward, there are likely further opportunities employ synthesis strategies other encoded modalities.

Language: Английский

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