Large scale meta-analysis of fragment-based screening campaigns: privileged fragments and complementary technologies

Area of Science:

• Drug Discovery
• Medicinal Chemistry
• Biophysics

Background:

• Fragment-based drug discovery (FBDD) utilizes fragment-based screening (FBS) to identify initial drug candidates.
• Integrating data from orthogonal screens in FBDD presents significant challenges.
• A comprehensive meta-analysis of 35 Novartis fragment-based campaigns was conducted.

Purpose of the Study:

• To determine fragment amenability for FBS.
• To compare fragment hits across different screening technologies and target classes.
• To optimize the pairing of FBS assay technologies for enhanced drug discovery.

Main Methods:

• Statistical meta-analysis of multidimensional FBS data from 35 campaigns.
• Utilized a generic 1400-fragment library against diverse target families.
• Employed various biophysical and biochemical screening techniques.

Main Results:

• Identified privileged substructures for specific target classes.
• Discovered fragments with broad activity across multiple targets.
• Revealed discrepancies between different screening technologies.
• Found that pairing biochemical and biophysical screens maximizes authentic hit discovery.

Conclusions:

• The study provides insights into fragment properties and screening technology performance.
• A strategy of pairing biochemical and biophysical assays is recommended for optimal FBS coverage.
• This meta-analysis refines FBDD screening protocols for increased efficiency.