Premium
Selection of DNA‐Encoded Dynamic Chemical Libraries for Direct Inhibitor Discovery
Author(s) -
Deng Yuqing,
Peng Jianzhao,
Xiong Feng,
Song Yinan,
Zhou Yu,
Zhang Jianfu,
Lam Fong Sang,
Xie Chao,
Shen Wenyin,
Huang Yiran,
Meng Ling,
Li Xiaoyu
Publication year - 2020
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.202005070
Subject(s) - drug discovery , bromodomain , computational biology , selection (genetic algorithm) , dna , brd4 , identification (biology) , negative selection , dna sequencing , fragment (logic) , biology , computer science , chemistry , combinatorial chemistry , genetics , bioinformatics , genome , gene , algorithm , machine learning , botany , histone
Dynamic combinatorial libraries (DCLs) is a powerful tool for ligand discovery in biomedical research; however, the application of DCLs has been hampered by their low diversity. Recently, the concept of DNA encoding has been employed in DCLs to create DNA‐encoded dynamic libraries (DEDLs); however, all current DEDLs are limited to fragment identification, and a challenging process of fragment linking is required after selection. We report an anchor‐directed DEDL approach that can identify full ligand structures from large‐scale DEDLs. This method is also able to convert unbiased libraries into focused ones targeting specific protein classes. We demonstrated this method by selecting DEDLs against five proteins, and novel inhibitors were identified for all targets. Notably, several selective BD1/BD2 inhibitors were identified from the selections against bromodomain 4 (BRD4), an important anti‐cancer drug target. This work may provide a broadly applicable method for inhibitor discovery.