In considering the reasons for the 100-fold increase in potency for CDK2 that was observed upon cyclizing 6 to give 5 the authors noted that, when docked into CDK2 and FLT3, the macrocyclic compound shows a salt bridge between an N-methylammonium group in the linker and an active site aspartic acid, an interaction that was not seen in models of the bound acyclic precursor. The authors therefore suggested that the observed increase in potency results from conformational preorganization due to macrocyclization which facilitates formation of the salt bridge. We note, however, that there is no apparent impediment to the N-methyl group in the acyclic precursor 6 forming this same salt bridge. Thus, if the modeling results can be relied upon, a hypothetical bound conformation of 6 in which the N-methylammonium engages in this salt bridge with the protein is in fact less stable (i.e. higher in free energy, corresponding to weaker binding) than the modeled structure that lacks this interaction. Consequently, the affinity increase upon macrocyclization would be even greater for this hypothetical salt bridge-containing complex of 6 than for the modeled complex of 6 that lacks the salt bridge. As such, the affinity enhancement cannot be attributed to the energy generated by formation of the salt bridge. Instead, whether or not the modeling is correct that the salt bridge forms only with the macrocyclic ligand, the affinity enhancement that accompanies macrocyclization must presumably be attributed to the reduction in entropy associated with freezing out the bond rotations required to constrain the compound in the correct orientation for binding, plus possibly the enthalpic effects of any interactions between the linker atoms and the protein. Experimental crystal structures would help test these suppositions.