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

Area of Science:

• Drug Discovery
• Computational Chemistry
• Biotechnology

Background:

• DNA-encoded library (DEL) technology is crucial for drug discovery but often limited by proprietary software.
• Lack of accessible tools hinders academic researchers and small biotech companies.
• Advanced computational methods are essential for maximizing DEL potential.

Purpose of the Study:

• Introduce DELi, an open-source informatics platform for DEL design, sequencing (NGS) decoding, and enrichment analysis.
• Demonstrate DELi's utility through the design and selection of a benzimidazole-based library against BRD4.
• Validate the effectiveness of DELi in identifying potent drug candidates.

Main Methods:

• Developed DELi, an open-source platform for DEL library design, NGS data decoding, and hit identification.
• Designed and synthesized a custom benzimidazole DEL library (UNC-DEL006).
• Performed selection experiments against Bromodomain-containing Protein 4 (BRD4) and analyzed results using DELi.

Main Results:

• DELi successfully designed a custom DEL library and decoded NGS data.
• Analysis identified top-performing compounds, leading to the synthesis of UNC 002-080.
• Synthesized UNC 002-080 confirmed as a nanomolar BRD4 binder via ITC, while a non-prioritized analog showed no binding.

Conclusions:

• DELi is an effective open-source tool for DNA-encoded library design and analysis.
• The platform facilitates the identification of high-affinity binders, exemplified by the BRD4 inhibitor.
• The open-source nature of DELi encourages community development and broader application in drug discovery.