<p>Ligand efficiency is a widely used
design parameter in drug discovery. It is calculated by scaling affinity by
molecular size and has a nontrivial dependency on the concentration unit used
to express affinity that stems from the inability of the logarithm function to
take dimensioned arguments. Consequently, perception of efficiency varies with
the choice of concentration unit and it is argued that the ligand efficiency
metric is not physically meaningful nor should it be considered to be a metric.
The dependence of ligand efficiency on the concentration unit can be eliminated
by defining efficiency in terms of sensitivity of affinity to molecular size
and this is illustrated with reference to fragment-to-lead optimizations. An
alternative to ligand efficiency for normalization of affinity with respect to
molecular size is presented. Group efficiency and fit quality are also examined
in detail from a physicochemical perspective. The importance of examining
relationships between affinity and molecular size directly is stressed
throughout this study. </p>