Biological diversity from a structurally diverse library: systematically scanning conformational space using a...

Area of Science:

• Medicinal Chemistry
• Drug Discovery
• Peptidomimetics

Background:

• Discovering bioactive peptide mimetics is challenging due to difficulties in transferring peptide binding elements to stable scaffolds.
• Maintaining bioactivity while improving metabolic stability is a key hurdle in peptide mimetic development.

Purpose of the Study:

• To develop a systematic scanning approach using a diverse library of pyranose-based peptidomimetics.
• To identify bioactive compounds targeting somatostatin (sst1-5) and melanin-concentrating hormone (MCH1) receptors.
• To guide future drug discovery projects by identifying specific chemoform preferences.

Main Methods:

• Designed and synthesized a library of 490 structurally diverse pyranose-based peptidomimetics.
• Systematically varied pyranose scaffold chirality and substitution patterns to achieve structural diversity.
• Screened the library in vitro for activity against somatostatin (sst1-5) and MCH1 receptors.

Main Results:

• Identified bioactive compounds for both somatostatin and MCH1 receptor targets.
• Observed specific chemoform preferences for each receptor target.
• Demonstrated the utility of the scanning approach for guiding drug discovery.

Conclusions:

• The pyranose-based peptidomimetic library provides a versatile platform for discovering bioactive compounds.
• Specific chemoform preferences offer valuable insights for rational drug design.
• This approach facilitates targeted drug discovery without requiring scaffold hopping.