Abstract
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. 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 and an alternative to ligand efficiency for normalization of affinity with respect to molecular size is presented.
Highlights
Ligand efficiency is a widely used design parameter in drug discovery
There are two ligand efficiencies in drug discovery and these can be seen as different manifestations of what might be called molecular size efficiency (MSE)
The findings from Kuntz et al [32] do not appear to provide insights that would be useful for the interpretation of the results shown in Fig. 3b and this reflects the fact that affinity measured against multiple targets was used for the analysis in that study
Summary
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. Ligand efficiency (LE) is, in essence, a good concept that is poorly served by a bad metric It was introduced [1] as “a useful metric for lead selection”, has been discussed at length in reviews [2,3,4,5,6] and is routinely tracked in drug discovery projects. One significant difficulty [14] in drug design is that unbound intracellular concentration [15, 16] cannot generally be measured for drugs in vivo
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