The Nature of Ligand Efficiency

29 October 2018, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


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.


ligand efficiency
group efficiency
Structure Activity Relationships
drug design metric
fragment-based lead discovery
fit quality
molecular recognition

Supplementary materials

pwk le oct2018 v1.0


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