Fragment-based drug discovery-the importance of high-quality molecule libraries

Area of Science:

• Medicinal Chemistry
• Drug Discovery
• Computational Chemistry

Background:

• Fragment-based drug discovery (FBDD) is a key complementary strategy to high-throughput screening (HTS).
• FBDD employs smaller, less complex molecules with higher atom-efficient binding compared to larger molecules used in HTS.
• This approach is particularly advantageous for optimizing leads against challenging drug targets.

Purpose of the Study:

• To review current perspectives on fragment library design in FBDD.
• To define desirable characteristics of fragment molecules from medicinal and computational chemistry viewpoints.
• To discuss emerging technologies and optimization strategies within FBDD.

Main Methods:

• Review of fragment library design principles.
• Analysis of fragment characteristics for medicinal and computational chemistry.
• Highlighting novel chemical and computational technologies in FBDD.
• Discussion of fragment hit optimization strategies.

Main Results:

• FBDD enables greater chemical space coverage with smaller libraries compared to HTS.
• Well-designed fragment libraries are crucial for optimal diversity and physicochemical properties.
• Emerging technologies are enhancing FBDD capabilities.
• Successful application of FBDD is demonstrated by the approval of KRAS^G12C inhibitor sotorasib.

Conclusions:

• FBDD is a powerful approach for drug discovery, especially for previously undruggable targets.
• Strategic library design and optimization are critical for FBDD success.
• The field is advancing with new technologies and successful clinical applications.