Comprehensive and High-Throughput Exploration of Chemical Space Using Broadband ¹⁹ F NMR-Based Screening

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Structural Biology

Background:

• Fragment-based lead discovery is crucial for identifying ligands for disease targets.
• Fluorine-detected NMR (¹⁹F NMR) is a sensitive and robust screening technique.
• Efficient chemical space exploration requires optimized fragment libraries and NMR methods.

Purpose of the Study:

• To develop a comprehensive method for assembling a high-quality fragment library.
• To screen for target-specific binders using an optimized NMR approach.
• To enable fast ligandability assessment of new targets.

Main Methods:

• Assembly of a diverse library of nearly 4000 fragments.
• Development of a novel broadband relaxation-edited ¹⁹F NMR experiment.
• Optimization of sample composition for maximal compound throughput and minimal measurement time.

Main Results:

• Successful creation of a high-quality, diverse fragment library.
• Screening of the library for target-specific binders within days.
• Demonstration of the NMR experiment's ability to cover the full chemical shift range of ¹⁹F motifs in a single measurement.

Conclusions:

• The developed method enables efficient fragment library assembly and screening.
• The novel NMR experiment facilitates rapid identification of diverse binders.
• This approach accelerates the assessment of target ligandability in drug discovery.