Bioactivity-guided navigation of chemical space

Area of Science:

• Chemical Biology
• Drug Discovery
• Bioinformatics

Background:

• Elucidating protein functions is crucial for understanding biological systems.
• Chemical perturbations offer unique advantages over genetic methods for studying protein function.
• Identifying relevant starting points in chemical space is challenging for designing effective compound libraries.

Purpose of the Study:

• To link chemical and biological space for designing biologically relevant compound collections.
• To develop a systematic approach for identifying suitable starting points for small-molecule synthesis.
• To generate hypotheses for compound library design and predict potential bioactivities.

Main Methods:

• Biology-Oriented Synthesis (BIOS) approach integrating chem- and bioinformatics.
• Protein Structure Similarity Clustering (PSSC) to identify similar ligand-binding sites.
• Scaffold trees (e.g., Structural Classification of Natural Products - SCONP) for hierarchical classification and navigation of chemical space.
• Utilizing software like "Scaffold Hunter" for chemical space analysis.

Main Results:

• BIOS effectively maps biologically relevant chemical and protein spaces.
• PSSC identifies protein binding sites with high structural similarity in their ligand-sensing cores.
• Scaffold trees facilitate the identification of novel starting points for library design.
• BIOS enables the synthesis of focused compound collections with high hit rates in biological screens.
• Identification of new ligand classes and chemical probes for various proteins.

Conclusions:

• The BIOS approach provides a robust strategy for designing targeted small-molecule libraries.
• Integrating protein structure and chemical scaffold analysis enhances the efficiency of drug discovery.
• BIOS facilitates the discovery of novel bioactive compounds and chemical probes for biological research.