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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AutoDesigner - Core Design, a De Novo Design Algorithm for Chemical Scaffolds: Application to the Design and Synthesis of Novel Selective Wee1 Inhibitors

Published: June 13, 2024

The hit identification stage of a drug discovery program generally involves the design novel chemical scaffolds with desired biological activity against target(s) interest. One common approach is scaffold hopping, which manual based on known matter. major limitation this narrow space exploration, can lead to difficulties in maintaining or improving activity, selectivity, and favorable property space. Another lack preliminary structure-activity relationship (SAR) data around these designs, could selecting suboptimal advance optimization. To address limitations, we propose AutoDesigner - Core Design (CoreDesign), de novo algorithm. Our cloud-integrated, algorithm for systematically exploring refining targets evaluates, optimizes vast range from millions billions molecules silico, following defined project parameters encompassing structural novelty, physicochemical attributes, potency, selectivity. In manner, CoreDesign generate also explore SAR each using FEP+ potency predictions. requires only single ligand quantifiable binding affinity an initial hypothesis, making it especially suited hit-identification where experimental often limited. validate real-world setting, applied novel, potent Wee1 inhibitors improved selectivity over PLK1. Starting ligand, rapidly explored 23 billion identify 1,342 series mean 4 compounds per scaffold. Importantly, all met predefined requirements. analyze large amount prioritize synthesis, utilize t-Distributed Stochastic Neighbor Embedding (t-SNE) plots silico properties. projections allowed us structurally 5-5 fused core meeting Several were synthesized assayed scaffold, displaying good excellent PLK1 results suggest that significantly speed up process increase probability success campaigns by allowing teams bring forward high-quality de-risked availability SAR.

Language: Английский

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The Facile Solid-Phase Synthesis of Thiazolo-Pyrimidinone Derivatives

Molecules, Journal Year: 2025, Volume and Issue: 30(2), P. 430 - 430

Published: Jan. 20, 2025

A thiazolo-pyrimidinone derivative library was developed through a facile solid-phase synthesis method. For the reaction, thiazolo[4,5-d]pyrimidin-7(6H)-one structure synthesized efficient Thorpe–Ziegler and cyclization reactions. The with diversity of three had total four steps 57 compounds. In addition, yield per step 65–97%, which very high. method compounds will be used to find biological activity thiazole structure–activity relationship.

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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Enhancing the Potential of Miniature-Scale DNA-Compatible Radical Reactions via an Electron Donor–Acceptor Complex and a Reversible Adsorption to Solid Support Strategy

Organic Letters, Journal Year: 2021, Volume and Issue: 23(19), P. 7381 - 7385

Published: Sept. 21, 2021

DNA-encoded library (DEL) technology is a powerful tool in the discovery of bioactive probe molecules and drug leads. Mostly, success DEL stems from molecular diversity chemical libraries. However, construction DELs has been restricted by idiosyncratic needs required low concentration (∼1 mM or less) intermediate. Here, we report visible-light-promoted on-DNA radical coupling reactions via an electron donor–acceptor (EDA) complex reversible adsorption to solid support (RASS) strategy. This protocol provides unique solution challenges increasing reactivity highly diluted DNA substrates reducing residues heavy metals photocatalysts. A series indole sulfone selenide derivatives were obtained with good quantitative conversions. It anticipated that these mild-condition will significantly improve find widespread utility construction.

Language: Английский

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