Rules for Potency Ligand Efficiency Measures

Other assays typically employed in the course of a drug design project include physicochemical binding assays (based on, for example, NMR or Biacore surface plasmon resonance methodologies), mode-of-action cell assays (e.g., employing a specific antibody-based biomarker readout of the target or a downstream target), and phenotypic assays (e.g., cell proliferation assays). 

Another risk factor in compoimd design is molecular size. Kuntz et al. [16] suggested the concept of ligand efficiency (LE), postulating that there should be a limit to what a single atom can contribute to potency, which in turn suggested that potency per heavy atom (or LE) shoidd be optimized. LE is typically defined as potency divided by the number of heavy atoms, that is, LE = plCso/HAC (HAC, heavy atom count). A scaled form may be used that has units of kcal/ 

A simple LE measure can be used to gauge which parts of an inhibitor contribute most to binding, for example, in a deconstruction exercise where the inhibitor is cut down in steps. Subsequently, once the most efficient core has been determined, LLE can be used to identify additions to the molecule that yield potency that is not lipophilicity-driven. 

As an example of the latter in drug design, we show the combined use of a size-based and a lipophilicity-based ligand efficiency measure in a project situation. 

Metric Abbreviation Definition(s) Typical target range Reference 

---