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Multipodal insulin mimetics built on adamantane or proline scaffolds
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SYSNO ASEP 0539200 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Multipodal insulin mimetics built on adamantane or proline scaffolds Author(s) Hajduch, Jan (UOCHB-X) RID
Fabre, Benjamin (UOCHB-X) ORCID
Klopp, Benjamin (UOCHB-X)
Pohl, Radek (UOCHB-X) RID, ORCID
Buděšínský, Miloš (UOCHB-X) RID, ORCID
Šolínová, Veronika (UOCHB-X) RID, ORCID
Kašička, Václav (UOCHB-X) RID, ORCID
Köprülüoglu, Cemal (UOCHB-X) ORCID, RID
Eyrilmez, Saltuk M. (UOCHB-X) ORCID, RID
Lepšík, Martin (UOCHB-X) RID, ORCID
Hobza, Pavel (UOCHB-X) RID, ORCID
Mitrová, Katarína (UOCHB-X)
Lubos, Marta (UOCHB-X) ORCID
Garre Hernández, María Soledad (UOCHB-X) ORCID
Jiráček, Jiří (UOCHB-X) RID, ORCIDArticle number 104548 Source Title Bioorganic Chemistry. - : Elsevier - ISSN 0045-2068
Roč. 107, Feb (2021)Number of pages 17 s. Language eng - English Country US - United States Keywords insulin receptor ; peptidomimetics ; scaffold ; solid-phase peptide synthesis ; hormone binding ; molecular dynamics OECD category Organic chemistry R&D Projects EF16_019/0000729 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Method of publishing Limited access Institutional support UOCHB-X - RVO:61388963 UT WOS 000618103400002 EID SCOPUS 85098193633 DOI 10.1016/j.bioorg.2020.104548 Annotation 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. Workplace Institute of Organic Chemistry and Biochemistry Contact asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Jana Procházková, Tel.: 220 183 418 Year of Publishing 2022 Electronic address https://doi.org/10.1016/j.bioorg.2020.104548
Number of the records: 1