Rationally minimizing natural product libraries using mass spectrometry.

Area of Science:

• Drug Discovery
• Natural Products Chemistry
• Mass Spectrometry

Background:

• Natural products are vital for novel drug discovery, but large, redundant libraries hinder high-throughput screening (HTS).
• Structural redundancy and re-discovery in natural product libraries increase screening time and costs.
• Existing natural product libraries face challenges in efficient HTS implementation.

Purpose of the Study:

• To develop a method for reducing natural product library size using mass spectrometry.
• To minimize bioactive loss while decreasing library volume for cost-effective drug discovery.
• To enhance bioassay hit rates and accelerate the identification of drug candidates.

Main Methods:

• Leveraged liquid chromatography-tandem mass spectrometry (LC-MS/MS) for spectral similarity analysis.
• Applied the method to a fungal extract collection to demonstrate library size reduction.
• Validated the approach for its broad applicability across different assays and natural product sources.

Main Results:

• Successfully reduced natural product library size with minimal loss of bioactive compounds.
• Achieved increased bioassay hit rates against microbial targets.
• Demonstrated broad applicability across various assays and natural product origins.

Conclusions:

• The developed LC-MS/MS spectral similarity method significantly reduces natural product library size.
• This strategy accelerates cost-effective natural product drug discovery.
• The method offers a broadly applicable solution for improving HTS efficiency.