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Increased Conformational Flexibility of a Macrocycle-Receptor Complex Contributes to Reduced Dissociation Rates
Max Planck Gesell, Chem Genom Ctr, Otto Hahn Str 15, D-44227 Dortmund, Germany..
Max Planck Inst Colloids & Interfaces, Dept Biomol Syst, Muhlenberg 1, D-14424 Potsdam, Germany.;Free Univ Berlin, Dept Biol Chem & Pharm, Takustr 3, D-14195 Berlin, Germany..ORCID iD: 0000-0002-8665-5512
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology. Max Planck Gesell, Chem Genom Ctr, Otto Hahn Str 15, D-44227 Dortmund, Germany..
Max Planck Inst Colloids & Interfaces, Dept Biomol Syst, Muhlenberg 1, D-14424 Potsdam, Germany.;Free Univ Berlin, Dept Biol Chem & Pharm, Takustr 3, D-14195 Berlin, Germany..
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2017 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 23, no 64, p. 16157-16161Article in journal (Refereed) Published
Abstract [en]

Constraining a peptide in its bioactive conformation by macrocyclization represents a powerful strategy to design modulators of challenging biomolecular targets. This holds particularly true for the development of inhibitors of protein-protein interactions which often involve interfaces lacking defined binding pockets. Such flat surfaces are demanding targets for traditional small molecules rendering macrocyclic peptides promising scaffolds for novel therapeutics. However, the contribution of peptide dynamics to binding kinetics is barely understood which impedes the design process. Herein, we report unexpected trends in the binding kinetics of two closely related macrocyclic peptides that bind their receptor protein with high affinity. Isothermal titration calorimetry, F-19 NMR experiments and molecular dynamics simulations reveal that increased conformational flexibility of the macrocycle-receptor complex reduces dissociation rates and contributes to complex stability. This observation has impact on macrocycle design strategies that have so far mainly focused on the stabilization of bioactive ligand conformations.

Place, publisher, year, edition, pages
John Wiley & Sons, 2017. Vol. 23, no 64, p. 16157-16161
Keywords [en]
F-19 NMR spectroscopy, binding kinetics, cyclic peptides, molecular dynamics simulation, peptidomimetics
National Category
Chemical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-339695DOI: 10.1002/chem.201702776ISI: 000417968100004PubMedID: 28777495OAI: oai:DiVA.org:uu-339695DiVA, id: diva2:1177846
Available from: 2018-01-26 Created: 2018-01-26 Last updated: 2018-01-26Bibliographically approved

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