Drugging challenging targets using fragment-based approaches.

Area of Science:

• Drug discovery and development
• Medicinal chemistry
• Structural biology

Background:

• Fragment-based approaches are a validated strategy in drug discovery.
• Early successes were primarily against protein kinases.
• Increasingly applied to diverse and challenging protein targets.

Purpose of the Study:

• To review the application of fragment-based approaches to diverse protein targets.
• To highlight successes where traditional methods have failed.
• To showcase the integration of experimental and computational screening methods.

Main Methods:

• Review of seven case studies demonstrating fragment-based drug discovery.
• Application of fragment screening to protein-protein interactions, RNA polymerase, and DNA-binding proteins.
• Integration of biophysical techniques and in silico screening.

Main Results:

• Fragment-based approaches have successfully targeted diverse and difficult proteins.
• Small fragment libraries outperformed large high-throughput screening (HTS) in some cases.
• Iterative synthetic elaboration of fragment hits led to increased potency.

Conclusions:

• Fragment-based drug discovery is versatile and effective for challenging targets.
• The combination of experimental and in silico methods enhances fragment-based approaches.
• Iterative optimization is key to building potency from initial fragment hits.