Zijian Liu; Baiyang Mu; Zhiqiang Duan; Xuan Wang; Xiaojie Lu Synth. Bio. J., 2024, 5, DOI: 10.12211/2096-8280.2024-008 https://doi.org/10.12211/2096-8280.2024-008
Abstract
DNA-Encoded Library (DEL) technology, as an emerging means of small molecule drug screening, has become an important and indispensable technology platform for new drug discovery and development. The technology incorporates many advantages from combinatorial chemistry, molecular biology, and chemical bioinformatics, which greatly improve the efficiency of compound library synthesis and screening. Meanwhile, driven by the development of nucleic acid-compatible chemical reactions and high-throughput sequencing technology, DEL technology has made remarkable progress and gradually become a fast, economical, and efficient high-throughput screening platform, and has been more and more widely used in seedling compounds screening by schools, research institutes, and large pharmaceutical companies. The success of a DEL screening relies heavily on the chemical space and structural diversity of the compound libraries, both of which are directly affected by the number of chemical reactions compatible with nucleic acids. Therefore, developing the on-DNA chemical reactions to continuously enrich the chemical toolbox for DEL synthesis and thus enhance the structural diversity and drug potential of the molecules in the libraries has been the focus in this field. In recent years, the number of on-DNA chemical reactions has increased significantly, greatly broadening the scope of chemical reactions available for DEL construction. Meanwhile, a series of novel reaction methods, such as photocatalysis, electrocatalysis, and biosynthesis, have also emerged in the application of on-DNA chemical reactions and further expanded the field that on-DNA chemical reactions can reach. In this paper, we systematically review the metal-catalyzed on-DNA chemical reactions in recent years, including C(sp2)-C(sp2) bond-formation reactions, C(sp3)-C(sp3) bond-formation reactions, C(sp2)-C(sp3) bond-formation reactions, and C(sp2)-X bond-formation reactions; the synthesis of on-DNA privileged heterocycles with single-ring, fused-ring, and spirocyclic rings that using target-oriented synthetic and diversity-oriented synthetic strategies; the research progress of photocatalytic and enzyme-catalyzed on-DNA chemical reactions. However, the currently developed on-DNA reactions also have problems, such as compatibility with nucleic acids and substrate suitability. In the future, it is important and promising to exploit more robust on-DNA reactions that can proceed under mild conditions, new types of on-DNA reactions, and the combination of high-throughput screening and computer-assisted on-DNA reactions.