DNA-Encoded Dynamic Chemical Library and Its Applications in Ligand Discovery

• DOI: 10.1021/jacs.8b09277
• Publication Date: 2018-11-01T11:47:18Z
• Authors: Yu Zhou; Chen Li; Jianzhao Peng; Liangxu Xie; Ling Meng; Qingrong Li; Jianfu Zhang; Xiang David Li; Xin Li; Xuhui Huang; Xiaoyu Li
• Keywords: Small Molecule Libraries; 0301 basic medicine; 03 medical and health sciences; Drug Discovery; Molecular Conformation; DNA; Ligands

Dynamic combinatorial library (DCL) has emerged as an efficient tool for ligand discovery and become important modality in biomedical research. However, the applications of DCLs have been significantly hampered by low diversity limited analytical methods capable processing large libraries. Here, we report a strategy that addressed this limitation can select cooperatively binding small-molecule pairs from large-scale dynamic Our approach is based on DNA-mediated hybridization, DNA-encoding, photo-cross-linking-based decoding scheme. To demonstrate generality performance approach, 10 000-member DNA-encoded prepared selected against six protein targets. Specific binders identified each target, validated biological activities ligands targets are implicated cellular functions including deacetylation sumoylation. Notably, series novel selective sirtuin-3 inhibitors developed. study circumvented major obstacle DCL may provide broadly applicable method