TY - JOUR
T1 - Increased Conformational Flexibility of a Macrocycle–Receptor Complex Contributes to Reduced Dissociation Rates
AU - Glas, Adrian
AU - Wamhoff, Eike Christian
AU - Krüger, Dennis M.
AU - Rademacher, Christoph
AU - Grossmann, Tom N.
PY - 2017/11/16
Y1 - 2017/11/16
N2 - 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, 19F 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.
AB - 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, 19F 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.
KW - F NMR spectroscopy
KW - binding kinetics
KW - cyclic peptides
KW - molecular dynamics simulation
KW - peptidomimetics
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U2 - 10.1002/chem.201702776
DO - 10.1002/chem.201702776
M3 - Article
AN - SCOPUS:85028672769
SN - 0947-6539
VL - 23
SP - 16157
EP - 16161
JO - Chemistry: A European Journal
JF - Chemistry: A European Journal
IS - 64
ER -