1. Identification of isoform/domain-selective fragments from the selection of DNA-encoded dynamic library
- Author
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Wenyin Shen, Yu Zhou, Yuqing Deng, Xiaoyu Li, and Jianzhao Peng
- Subjects
Gene isoform ,Protein family ,High-throughput screening ,Clinical Biochemistry ,Pharmaceutical Science ,Computational biology ,Ligands ,Biochemistry ,Chemical library ,Small Molecule Libraries ,chemistry.chemical_compound ,Protein Domains ,Sirtuin 1 ,Drug Discovery ,Dynamic combinatorial chemistry ,Humans ,Molecular Biology ,Molecular Structure ,Drug discovery ,Organic Chemistry ,Nuclear Proteins ,DNA ,Ligand (biochemistry) ,Bromodomain ,chemistry ,Molecular Medicine - Abstract
DNA-encoded chemical library (DEL) has emerged to be a powerful ligand screening technology in drug discovery. Recently, we reported a DNA-encoded dynamic library (DEDL) approach that combines the principle of traditional dynamic combinatorial library (DCL) with DEL. DEDL has shown excellent potential in fragment-based ligand discovery with a variety of protein targets. Here, we further tested the utility of DEDL in identifying low molecular weight fragments that are selective for different isoforms or domains of the same protein family. A 10,000-member DEDL was selected against sirtuin-1, 2, and 5 (SIRT1, 2, 5) and the BD1 and BD2 domains of bromodomain 4 (BRD4), respectively. Albeit with modest potency, a series of isoform/domain-selective fragments were identified and the corresponding inhibitors were derived by fragment linking.
- Published
- 2021
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