We explore the question of what are the best ligands for macromolecular tar
gets. A survey of experimental data on a large number of the strongest-bind
ing ligands indicates that the free energy of binding increases with the nu
mber of nonhydrogen atoms with an initial slope of approximate to-1.5 kcal/
mol (1 cal = 4.18 J) per atom. For ligands that contain more than 15 nonhyd
rogen atoms, the free energy of binding increases very little with relative
molecular mass; This nonlinearity is largely ascribed to nonthermodynamic
factors. An analysis of the dominant interactions suggests that van der Waa
ls interactions and hydrophobic effects provide a reasonable basis for unde
rstanding binding affinities across the entire set of ligands. Interesting
outliers that bind unusually strongly on a per atom basis include metal ion
s, covalently attached ligands, and a few well known complexes such as biot
in-avidin.