Fragment-based drug discovery: A graphical review.

Area of Science:

• Medicinal Chemistry
• Structural Biology
• Drug Discovery

Background:

• Fragment-based drug discovery (FBDD) is a powerful strategy for identifying novel drug leads.
• It offers advantages for challenging or previously undruggable targets where traditional screening methods fail.
• FBDD identifies low molecular weight fragments (<300 Da) that bind weakly to biological targets.

Purpose of the Study:

• To illustrate the modern FBDD workflow.
• To highlight the integration of experimental and computational methods in FBDD.
• To showcase innovations accelerating drug discovery cycles.

Main Methods:

• Detection of fragment-target interactions using sensitive biophysical techniques (NMR, X-ray crystallography, SPR).
• Structure-guided optimization of fragment hits through growing, linking, or merging strategies.
• Integration of experimental data with computational methods, including AI/ML.

Main Results:

• FBDD successfully generates potent leads from weakly binding fragments.
• Innovations in library design and screening platforms enhance discovery efficiency.
• Case studies of FDA-approved drugs (Vemurafenib, Venetoclax) demonstrate FBDD's success.

Conclusions:

• FBDD is a mature and effective approach for drug discovery, particularly for challenging targets.
• The integration of AI/ML and advanced technologies is further accelerating FBDD.
• FBDD continues to evolve, pushing the boundaries of developing transformative medicines.