創薬のためのDNAライブラリ設計戦略を提案(Researchers Highlight Rational Design Strategies in DNA-encoded Libraries for Drug Discovery)

2025-09-01

2025-08-22 中国科学院(CAS)

中国科学院上海薬物研究所(SIMM)の盧小杰研究員らは、DNAエンコード化学ライブラリ(DEL)の合理的設計戦略を総説としてまとめ、創薬研究における新たな方向性を提示した(Angewandte Chemie International Edition掲載)。DELはDNAバーコード化により大規模な化合物スクリーニングを可能にするが、現在は「量」から「質」重視へと変革が進んでいる。フラグメントベースDELは小分子断片を導入し、結合部位探索や断片成長・結合を通じて高親和性リガンドを効率的に生成する。共有結合型DELはアクリルアミドやスルホニルフルオリドなどの求電子基を組み込み、標的残基(例:システイン)と不可逆的に結合、低親和性相互作用も捕捉できるため「ドラックできない」標的への応用拡大が期待される。また、特定のタンパク質ファミリーや機能ドメインに焦点を当てたフォーカス型DELは、命中率やヒット品質を向上させる。これら戦略は、構造多様性の拡張と選択性向上を両立させ、マルチターゲット創薬や難標的介入に大きな可能性を拓く。

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創薬のためのDNAエンコードライブラリーにおける合理的な設計戦略 Rational Design Strategies in DNA-Encoded Libraries for Drug Discovery

Xudong Wang, Linjie Li, Xuanjing Shen, Prof. Xiaojie Lu
Angewandte Chemie International Edition Published: 25 July 2025
DOI:https://doi.org/10.1002/anie.202511839

Graphical Abstract

This review highlights recent advances in rational DNA-encoded library (DEL) design, focusing on fragment-based DELs, covalent DELs, and focused DELs. These innovations shift DELs from empirical screening to a more strategic, hypothesis-driven approach, enhancing hit quality and drug discovery efficiency.

Abstract

DNA-encoded libraries (DELs) have emerged as a powerful and cost-effective platform for high-throughput screening, enabling the rapid identification of small-molecule ligands against a wide range of biological targets. However, traditional DEL approaches often rely on empirical and broad-based library construction, which can lead to low hit rates, off-target interactions, and limited chemical diversity around pharmaceutically relevant motifs. Recent technological advances have sought to address these limitations, shifting DELs from a largely blind screening tool to a more rational and precision-oriented strategy. In this review, we systematically examine the evolution of DEL methodologies, with a particular focus on innovations in library design that enhance hit quality and screening efficiency. Specifically, we highlight the emergence of fragment-based DEL strategies for exploring chemical space with minimal structures, the incorporation of covalent warheads to enable irreversible binding to specific residues, and the development of focused DELs tailored to particular protein families or binding motifs. Together, these advances mark a shift from blind, empirical screening toward a more strategic and hypothesis-driven application of DEL technology.