Ligand binding to nucleic acids and proteins: Does selectivity increase with strength?

The possible relation of strength and selectivity of ligand binding to biomacromolecules and its theoretical limitation is discussed and illustrated with some examples. It is shown that a linear correlation between selectivity and affinity may be expected on the basis of thermodynamic principles, which also imply that multivalency is as important for selectivity as for affinity enhancement. That strictly linear correlations are often not observed is, apart form statistical problems, mostly due to interactions which may remain constant only at some sites but can differ significantly at other sites, which, e.g., dominate the affinity. Nevertheless, some drugs exhibit in line with theory at the same time a peak affinity and selectivity, such as etonitazene with different opioid receptors. Double-stranded nucleic acids feature relative stable and uniform structures and therefore show relatively good correlations with simple polyamines as ligands and RNA or DNA model receptors. Metalloproteins possess strong binding centers with additional discrimination sites, and can exhibit linear correlations, at least with structurally related metalloproteinases and their inhibitors.