Experiences in fragment-based lead discovery.

Area of Science:

• Drug discovery and development
• Biophysics
• Medicinal chemistry

Background:

• Fragment-based drug discovery (FBDD) is a powerful approach for identifying novel drug leads.
• Over the past decade, Vernalis has accumulated significant experience in applying FBDD methods.
• A variety of biological targets have been investigated using these techniques.

Purpose of the Study:

• To summarize Vernalis's decade-long experience in developing and applying FBDD methods.
• To highlight the practical aspects of biophysical techniques used in FBDD.
• To discuss strategies for fragment selection and optimization into lead compounds.

Main Methods:

• Utilized various biophysical techniques including surface plasmon resonance (SPR), differential scanning fluorimetry (DSF), isothermal titration calorimetry, nuclear magnetic resonance (NMR), and X-ray crystallography.
• Applied these methods to identify small molecules (fragments) that bind to diverse biological targets.
• Developed criteria and strategies for selecting and optimizing initial fragment hits.

Main Results:

• Successfully identified and characterized fragment binders for multiple targets using a suite of biophysical methods.
• Demonstrated the practical utility and challenges of different biophysical techniques in fragment screening.
• Established effective strategies for fragment evolution from initial binders to potent lead compounds.

Conclusions:

• Fragment-based discovery is a viable and effective strategy for drug development.
• The judicious application of biophysical techniques is crucial for successful fragment identification and characterization.
• Strategic fragment evolution is key to translating initial fragment hits into viable drug candidates.