Fragment-Based Drug Discovery: Advancing Fragments in the Absence of Crystal Structures.

Area of Science:

• Drug discovery and development
• Structural biology
• Medicinal chemistry

Background:

• Fragment-based drug discovery (FBDD) integrates screening, structural biology, and medicinal chemistry.
• X-ray crystallography is standard for protein-ligand complex structures but challenging for low-affinity fragments.

Purpose of the Study:

• To discuss strategies for fragment evolution when protein-fragment crystal structures are unavailable.
• To guide initial fragment hits towards obtaining crystal structures for optimization.

Main Methods:

• Utilizing alternative structural techniques like NMR spectroscopy.
• Employing molecular modeling and computational approaches.
• Applying various chemical strategies for fragment advancement.

Main Results:

• The discussed strategies enable fragment evolution without direct protein-fragment complex structures.
• These approaches facilitate the progression of weak fragment hits.
• The ultimate goal is to reach a stage amenable to X-ray crystallography.

Conclusions:

• Fragment evolution is achievable even without initial crystal structures.
• A combination of structural and chemical methods can overcome early-stage FBDD challenges.
• Successful fragment advancement leads to structures suitable for detailed optimization.