Multipodal insulin mimetics built on adamantane or proline scaffolds

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Biophysics

Background:

• Multi-orthogonal molecular scaffolds serve as foundational structures for bioactive compounds.
• Designing effective peptide hormone mimetics requires careful consideration of scaffold and peptide modifications.

Purpose of the Study:

• To synthesize and evaluate adamantane and proline-based scaffolds for creating insulin mimetics.
• To investigate the impact of scaffold structure and peptide flexibility on insulin receptor binding affinity.

Main Methods:

• Solid-phase synthesis of four tri-orthogonal scaffolds (adamantane or proline-based).
• Preparation of model insulin mimetics with two distinct peptides attached to the scaffolds.
• Binding affinity assays to determine dissociation constants (K_d) for insulin receptor interaction.
• Molecular dynamics simulations and molecular modeling to elucidate binding modes and flexibility effects.

Main Results:

• Adamantane-derived insulin mimetics demonstrated superior binding affinity (K_d = 0.5 μM) compared to proline-derived mimetics (K_d = 15-38 μM).
• Molecular dynamics simulations indicated that flexible spacers enhance binding affinity by increasing conformational adaptability.
• Molecular modeling provided insights into potential binding interactions with the insulin receptor.

Conclusions:

• The central scaffold's structure significantly influences the binding efficacy of peptide hormone mimetics.
• Peptide flexibility, modulated by spacers, plays a crucial role in achieving high binding affinity to the insulin receptor.
• Diverse scaffold designs should be explored for optimizing the development of novel peptide hormone mimetics.