Using biological performance similarity to inform disaccharide library design

Area of Science:

• Medicinal Chemistry
• Chemical Biology
• Drug Discovery

Background:

• Designing effective small-molecule discovery libraries requires understanding how synthesis choices impact biological activity.
• Stereochemistry is a critical structural feature that can significantly influence a molecule's biological performance.

Purpose of the Study:

• To develop methods for assessing the impact of stereochemical variations on the biological performance of small-molecule libraries.
• To identify which stereochemical features best predict similar biological performance across multiple assays.
• To guide synthesis decisions for future library development.

Main Methods:

• Preparation of a disaccharide library with systematic stereochemical variations.
• Assaying the library for diverse biological effects.
• Development of data-analysis methods to assess performance similarity and identify key stereochemical drivers.

Main Results:

• Established methods to quantitatively assess performance similarity between library members across multiple biological assays.
• Identified specific stereochemical features that correlate with similar or varied biological outcomes.
• Demonstrated a data-driven approach to link chemical structure to biological function.

Conclusions:

• The developed data-analysis approach can generalize to other chemical descriptors and biological assays.
• Prioritizing synthesis based on structure-performance relationships enhances second-generation library design.
• Identifying features causing performance variation guides the development of novel synthetic methodologies for optimal screening collections.