Fragment based drug discovery: practical implementation based on ¹⁹F NMR spectroscopy

Area of Science:

• Medicinal Chemistry
• Structural Biology
• Biophysics

Background:

• Fragment-based drug discovery (FBDD) is crucial for identifying novel therapeutics.
• Nuclear Magnetic Resonance (NMR) spectroscopy is a powerful technique for FBDD.
• Traditional proton-based NMR methods are well-established, but (19)F NMR offers unique advantages.

Purpose of the Study:

• To demonstrate the broad applicability of (19)F NMR-based fragment screening.
• To highlight (19)F NMR as a tool for sensitive fragment hit detection.
• To showcase its utility in structure-activity relationship (SAR) development and druggability assessment.

Main Methods:

• Utilizing (19)F NMR for fragment screening against protein targets.
• Applying (19)F NMR for rapid SAR development using diverse compound libraries.
• Employing (19)F NMR to evaluate the druggability of protein targets.

Main Results:

• Demonstrated sensitive detection of fragment hits using (19)F NMR.
• Showcased rapid SAR development from hit to lead stage.
• Provided efficient assessment of target protein druggability.

Conclusions:

• (19)F NMR-based fragment screening offers a versatile and efficient approach in drug discovery.
• This technique facilitates sensitive hit identification, rapid lead optimization, and target druggability evaluation.
• (19)F NMR expands the utility of fragment screening beyond targeting specifically "fluorophilic" protein sites.