Journal: bioRxiv

Article Title: DNA-encoded Library Screening Uncovers Potent DNMT2 Inhibitors Targeting a Cryptic Allosteric Binding Site

doi: 10.1101/2025.01.15.632061

Figure Lengend Snippet: ( A ) DELopen screening workflow. DELopen libraries consist of 4.2B compounds encoded by individual DNA barcodes. During affinity selection, small molecule-DNA-conjugates are enriched, while non-binders are washed away. The pipeline’s last step is the sequencing and decoding of new ligand structures. ( B ) Conditions used during the DELopen screening: In condition A native DNMT2 without additives was used; condition B: DNMT2 and SAH (100 µM) were mixed to block the SAH binding site; condition C: DNMT2 was incubated with tRNA Asp (10 µM). Most full-length molecules were enriched in condition ABC (unaffected by competitors), from which 5 selected compounds 1 – 5 were chosen for off-DNA synthesis and downstream characterization. ( C ) Enriched triazine-based compounds selected from ABC. ( D ) Peptidomimetic compounds enriched in ABC and chosen for further study. Building blocks BB1–BB4 are highlighted accordingly.

Article Snippet: DEL screening against human DNMT2 protein was performed with the fourth generation DELopen library (4.2 billion compounds, 27 sub-libraries) by WuXi AppTec.

Techniques: Selection, Sequencing, Blocking Assay, Binding Assay, Incubation, DNA Synthesis