Learning from our mistakes: the 'unknown knowns' in fragment screening

Area of Science:

• Medicinal Chemistry
• Drug Discovery
• Biochemistry

Background:

• Fragment-based lead discovery (FBLD) is a widely adopted drug discovery approach.
• FBLD involves identifying small molecular fragments and elaborating them into drug leads.
• Initial fragment affinities are often low, challenging detection methods.

Purpose of the Study:

• To discuss common artifacts, false positives, and false negatives in FBLD.
• To provide suggestions for avoiding these detection issues.
• To highlight the applicability of these lessons to high-throughput screening (HTS).

Main Methods:

• Review and analysis of common challenges in FBLD detection.
• Identification of artifacts, false positives, and false negatives.
• Development of strategies to mitigate detection errors.

Main Results:

• Detection methods in FBLD are frequently pushed to their limits.
• Unrecognized artifacts, false positives, and false negatives are common issues.
• Proactive strategies can help mitigate these problems.

Conclusions:

• Addressing detection challenges is crucial for successful FBLD.
• The insights provided can improve the reliability of FBLD and HTS.
• Careful method validation is essential for robust drug lead identification.