Selection of DNA-Encoded Dynamic Chemical Libraries for Direct Inhibitor Discovery

Deng，Yuqing1; Peng，Jianzhao1,2; Xiong，Feng1; Song，Yinan1; Zhou，Yu1; Zhang，Jianfu1; Lam，Fong Sang1; Xie，Chao1; Shen，Wenyin1; Huang，Yiran1; Meng，Ling1; Li，Xiaoyu1

2020

10.1002/anie.202005070

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION   影响因子和分区

1433-7851

1521-3773

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.

DNA DNA-encoded dynamic libraries drug discovery dynamic combinatorial libraries high-throughput screening

SCI ; IC ; EI

英语

NI论文

其他

Research Grants Council of the Hong Kong SAR[AoE/P-705/16][17321916][17302817][17301118][17111319] ; National Natural Science Foundation of China[21572014][21877093][91953119]

Chemistry

Chemistry, Multidisciplinary

WOS:000539658100001

WILEY-V C H VERLAG GMBH

20202408828862

Libraries ; Ligands ; Proteins

Biological Materials and Tissue Engineering:461.2 ; Physical Chemistry:801.4 ; Organic Compounds:804.1 ; Libraries:903.4.1

CHEMISTRY

2-s2.0-85086318865

Scopus

1.Department of Chemistry and the State Key Laboratory of Synthetic Chemistry,The University of Hong Kong,Laboratory for Synthetic Chemistry and Chemical Biology of Health@InnoHK of Innovation and Technology Commission,Pokfulam Road,Hong Kong
2.Department of Chemistry,Southern University of Science and Technology China,Shenzhen,1088 Xueyuan Road,China

Deng，Yuqing,Peng，Jianzhao,Xiong，Feng,et al. Selection of DNA-Encoded Dynamic Chemical Libraries for Direct Inhibitor Discovery[J]. ANGEWANDTE CHEMIE-INTERNATIONAL EDITION,2020,59(35):14965-14972.

Deng，Yuqing.,Peng，Jianzhao.,Xiong，Feng.,Song，Yinan.,Zhou，Yu.,...&Li，Xiaoyu.(2020).Selection of DNA-Encoded Dynamic Chemical Libraries for Direct Inhibitor Discovery.ANGEWANDTE CHEMIE-INTERNATIONAL EDITION,59(35),14965-14972.

Deng，Yuqing,et al."Selection of DNA-Encoded Dynamic Chemical Libraries for Direct Inhibitor Discovery".ANGEWANDTE CHEMIE-INTERNATIONAL EDITION 59.35(2020):14965-14972.