Multipodal insulin mimetics built on adamantane or proline scaffolds

0539200 - ÚOCHB 2022 RIV US eng J - Journal Article
Hajduch, Jan - Fabre, Benjamin - Klopp, Benjamin - Pohl, Radek - Buděšínský, Miloš - Šolínová, Veronika - Kašička, Václav - Köprülüoglu, Cemal - Eyrilmez, Saltuk M. - Lepšík, Martin - Hobza, Pavel - Mitrová, Katarína - Lubos, Marta - Garre Hernández, María Soledad - Jiráček, Jiří
Multipodal insulin mimetics built on adamantane or proline scaffolds.
Bioorganic Chemistry. Roč. 107, Feb (2021), č. článku 104548. ISSN 0045-2068. E-ISSN 1090-2120
R&D Projects: GA MŠMT(CZ) EF16_019/0000729
Institutional support: RVO:61388963
Keywords : insulin receptor * peptidomimetics * scaffold * solid-phase peptide synthesis * hormone binding * molecular dynamics
OECD category: Organic chemistry
Impact factor: 5.307, year: 2021
Method of publishing: Limited access
https://doi.org/10.1016/j.bioorg.2020.104548

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.
Permanent Link: http://hdl.handle.net/11104/0317235