Covalent Capture and Selection of DNA‐Encoded Chemical Libraries via Photo‐Activated Lysine‐Selective Crosslinkers

Wei, Haimei; Zhang, Tianyang; Li, Yangfeng; Zhang, Gong; Li, Yizhou

doi:10.1002/asia.202300652

Chemistry An Asian Journal

2023

DOI: 10.1002/asia.202300652

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Covalent Capture and Selection of DNA‐Encoded Chemical Libraries via Photo‐Activated Lysine‐Selective Crosslinkers

Haimei Wei,

Tianyang Zhang,

Yangfeng Li

et al.

Abstract: Covalent crosslinking probes have arisen as efficient toolkits to capture and elucidate biomolecular interaction networks. Exploiting the potential of crosslinking in DNA‐encoded chemical library (DEL) selection methods significantly boosted bioactive ligand discovery in complex physiological contexts. Herein, we incorporated o‐nitrobenzyl alcohol (o‐NBA) as a photo‐activated lysine‐selective crosslinker into divergent DEL formats and achieved covalent capture of ligand‐target interactions featuring improved c… Show more

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2024

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Cited by 2 publications

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Challenges and Prospects of DNA-Encoded Library Data Interpretation

Wichert,

Guasch,

Franzini

2024

Chem. Rev.

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DNA-encoded library (DEL) technology is a powerful platform for the efficient identification of novel chemical matter in the early drug discovery process enabled by parallel screening of vast libraries of encoded small molecules through affinity selection and deep sequencing. While DEL selections provide rich data sets for computational drug discovery, the underlying technical factors influencing DEL data remain incompletely understood. This review systematically examines the key parameters affecting the chemical information in DEL data and their impact on hit triaging and machine learning integration. The need for rigorous data handling and interpretation is emphasized, with standardized methods being critical for the success of DEL-based approaches. Major challenges include the relationship between sequence counts and binding affinities, frequent hitters, and the influence of factors such as inhomogeneous library composition, DNA damage, and linkers on binding modes. Experimental artifacts, such as those caused by protein immobilization and screening matrix effects, further complicate data interpretation. Recent advancements in using machine learning to denoise DEL data and predict drug candidates are highlighted. This review offers practical guidance on adopting best practices for integrating robust methodologies, comprehensive data analysis, and computational tools to improve the accuracy and efficacy of DEL-driven hit discovery.

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Challenges and Prospects of DNA-Encoded Library Data Interpretation

Wichert,

Guasch,

Franzini

2024

Chem. Rev.

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Translation of Deoxyribonucleic Acid into Synthetic Alpha Helical Peptides for Darwinian Evolution

Dockerill,

Sabale,

Russo

et al. 2024

JACS Au

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DNA-encoded libraries connect the phenotypes of synthetic molecules to a DNA barcode; however, most libraries do not tap into the potential of Darwinian evolution. Herein, we report a DNA-templated synthesis (DTS) architecture to make peptides that are stabilized into α-helical conformations via head-to-tail supramolecular cyclization. Using a pilot library targeting MDM2, we show that repeated screening can amplify a binder from the lowest abundance in the library to a ranking that correlates to binding affinity. The study also highlights the need to design libraries such that the chemistry avoids biases from the heterogeneous yield in DTS.

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Covalent Capture and Selection of DNA‐Encoded Chemical Libraries via Photo‐Activated Lysine‐Selective Crosslinkers

Cited by 2 publications

References 58 publications

Challenges and Prospects of DNA-Encoded Library Data Interpretation

Challenges and Prospects of DNA-Encoded Library Data Interpretation

Translation of Deoxyribonucleic Acid into Synthetic Alpha Helical Peptides for Darwinian Evolution

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