DNA Barcoding a Complete Matrix of Stereoisomeric Small Molecules

Area of Science:

• Synthetic organic chemistry
• Medicinal chemistry
• Chemical biology

Background:

• DNA-encoded libraries (DELs) synthesis faces challenges in incorporating stereochemical diversity and complexity.
• Modern synthetic organic chemistry capabilities are not fully utilized in DEL construction.

Purpose of the Study:

• To design, construct, and validate a novel DNA-encoded library (DOS-DEL-1) of chiral 2,3-disubstituted azetidines and pyrrolidines.
• To demonstrate a strategy for synthesizing DELs with scaffold-based stereochemical diversity and complexity.
• To validate the library's utility in drug discovery screens.

Main Methods:

• Stereospecific C-H arylation for scaffold construction.
• Improved on-DNA Suzuki reaction for library quality.
• Tanimoto multifusion similarity analysis for property assessment.
• Validation screens against horseradish peroxidase and carbonic anhydrase IX.
• Development of a Poisson-based statistical framework for data analysis.

Main Results:

• Construction of DOS-DEL-1, a library of 107,616 DNA-barcoded compounds.
• Most library members exhibit drug-like physicochemical properties.
• The library shows greater resemblance to diversity-oriented synthesis collections.
• Successful identification of potent carbonic anhydrase inhibitors (IC50 = 20.1–68.7 nM) from validation screens.

Conclusions:

• The developed strategy enables the synthesis of DELs with significant stereochemical diversity and complexity.
• This approach does not require novel DNA-compatible chemistry, leveraging existing synthetic methods.
• The validated library and screening framework facilitate efficient drug discovery, exemplified by potent inhibitor identification.