Hajduch J(1), Fabre B(1), Klopp B(1), Pohl R(1), Buděšínský M(1), Šolínová V(1), Kašička V(1), Köprülüoglu C(2), Eyrilmez SM(2), Lepšík M(1), Hobza P(2), Mitrová K(1), Lubos M(1), Hernández MSG(1), Jiráček J(3). Author information:
(1)The Institute of Organic Chemistry and Biochemistry, Czech Academy of
Sciences, Flemingovo n. 2, 16610 Praha 6, Czech Republic.
(2)The Institute of Organic Chemistry and Biochemistry, Czech Academy of
Sciences, Flemingovo n. 2, 16610 Praha 6, Czech Republic; Regional Centre of
Advanced Technologies and Materials, Department of Physical Chemistry, Palacký
University, 77146 Olomouc, Czech Republic.
(3)The Institute of Organic Chemistry and Biochemistry, Czech Academy of
Sciences, Flemingovo n. 2, 16610 Praha 6, Czech Republic. Electronic address:
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.
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