What is ligand efficiency, and why do teams track it?

Why

Hopkins, Groom and Alex proposed the metric to compare starting points of different sizes. A fragment with micromolar affinity and 12 heavy atoms may be a far better start than a 45-atom hit at 100 nanomolar, because the fragment extracts more binding energy per atom and has room to grow. Optimization usually adds atoms, so tracking efficiency reveals whether the added atoms are doing useful work or just filling space.

Related metrics adjust for lipophilicity, since potency gained by making a molecule greasier often costs solubility, metabolic stability and selectivity. Lipinski and colleagues already observed that screening-era leads were heavier and more lipophilic than earlier ones, which is the pattern these metrics are designed to catch. The caveats are real.

Efficiency depends on the assay and the affinity measurement, so values from different assays are not comparable. Targets differ in what is achievable, with flat protein-protein interfaces supporting lower efficiency than enzyme pockets. The metric says nothing about selectivity, synthesis cost or whether the binding mode is useful.

It is a steering aid during optimization, not a selection criterion on its own.