Open-Source DNA-Encoded Library Package for Design, Decoding, and Analysis: DELi

Wellnitz, J.; Novy, B. C.; Maxfield, T.; Zhilinskaya, I.; Lin, J.; Axtman, M.; Leisner, T.; Norris-Drouin, J. L.; Hardy, B. P.; Pearce, K. H.; Popov, K. I.

doi:10.1101/2025.02.25.640184

bioRxiv · 10.1101/2025.02.25.640184

Open-Source DNA-Encoded Library Package for Design, Decoding, and Analysis: DELi

Wellnitz, J.·Novy, B. C.·Maxfield, T.·Zhilinskaya, I.·Lin, J.·Axtman, M.·Leisner, T.·Norris-Drouin, J. L.·Hardy, B. P.·Pearce, K. H.·Popov, K. I.

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Abstract

DNA-encoded library (DEL) technology has become a powerful tool in modern drug discovery. Fully harnessing its potential requires the use of extensive computational methodologies, which are often available only through proprietary software. This restricts accessibility for small teams lacking robust informatics support, hindering the growth of the technology. Here, we present DELi, an open-source DEL informatics platform designed for library design, NGS decoding and calling, and enrichment analysis. DELi supports a simple and easy to understand configuration setup to present a straightforward user interface. To showcase its capabilities, we used DELi to design an in-house custom, benzimidazole-based DEL (UNC DEL006), and performed proof-of-concept selection experiments against Bromodomain-containing Protein 4 (BRD4). The DELi decoding and analysis modules identified top-performing compounds, leading to the off-DNA synthesis of UNC11951, which was confirmed as a nanomolar BRD4 binder via isothermal titration calorimetry (ITC) and differential scanning fluorimetry (DSF). These results demonstrate DELi as an effective tool for DEL design and analysis. Furthermore, its open-source nature will promote ongoing development and contributions from the DEL community to expand its applications and capabilities, making DEL technology more widely accessible. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=94 SRC="FIGDIR/small/640184v3_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@1d4ca88org.highwire.dtl.DTLVardef@13cb4feorg.highwire.dtl.DTLVardef@8ea7ecorg.highwire.dtl.DTLVardef@1b294fc_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Wellnitz, J., Novy, B. C., Maxfield, T., Zhilinskaya, I., Lin, J., Axtman, M., Leisner, T., Norris-Drouin, J. L., Hardy, B. P., Pearce, K. H., Popov, K. I.. 2025-03-01. Open-Source DNA-Encoded Library Package for Design, Decoding, and Analysis: DELi. https://doi.org/10.1101/2025.02.25.640184

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