Multipodal insulin mimetics built on adamantane or proline scaffolds
| Autor: | Benjamin Klopp, Benjamin Fabre, Jan Hajduch, Radek Pohl, María Soledad Garre Hernández, Katarína Mitrová, Saltuk M. Eyrilmez, Martin Lepšík, Marta Lubos, Miloš Buděšínský, Jiří Jiráček, Pavel Hobza, Václav Kašička, Cemal Köprülüoğlu, Veronika Šolínová |
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| Rok vydání: | 2020 |
| Předmět: |
Scaffold
Molecular model Proline Peptidomimetic Adamantane Molecular Dynamics Simulation 01 natural sciences Biochemistry chemistry.chemical_compound Drug Discovery Animals Humans Insulin Insulin mimetic Protein Structure Quaternary Molecular Biology Solid-Phase Synthesis Techniques Binding Sites biology 010405 organic chemistry Protein Stability Organic Chemistry Stereoisomerism Combinatorial chemistry Receptor Insulin 0104 chemical sciences Rats 010404 medicinal & biomolecular chemistry Insulin receptor Kinetics chemistry biology.protein Protein Binding |
| Zdroj: | Bioorganic chemistry. 107 |
| ISSN: | 1090-2120 |
| Popis: | Multi-orthogonal molecular scaffolds can be applied as core structures of bioactive compounds. Here, we prepared four tri-orthogonal scaffolds based on adamantane or proline skeletons. The scaffolds were used for the solid-phase synthesis of model insulin mimetics bearing two different peptides on the scaffolds. We found that adamantane-derived compounds bind to the insulin receptor more effectively (Kd value of 0.5 μM) than proline-derived compounds (Kd values of 15–38 μM) bearing the same peptides. Molecular dynamics simulations suggest that spacers between peptides and central scaffolds can provide greater flexibility that can contribute to increased binding affinity. Molecular modeling showed possible binding modes of mimetics to the insulin receptor. Our data show that the structure of the central scaffold and flexibility of attached peptides in this type of compound are important and that different scaffolds should be considered when designing peptide hormone mimetics. |
| Databáze: | OpenAIRE |
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