Lipophilic efficiency (LipE), also referred to as ligand-lipophilicity efficiency (LLE) represents the relationship between the target binding of interest (measured as IC50 or EC50) and the lipophilicity (partition coefficient, logP, or distribution coefficient, logD) of the compound.
When identifying suitable chemical starting points for optimisation to drug-like molecules, it can be advantageous to use small, hydrophilic molecules which offer good potency without excess lipophilicity. Increased lipophilicity can result in increased binding due to non-specific interactions, and thus give a greater likelihood of undesired off-target effects. When comparing a series of hit compounds in a drug discovery programme, compounds with high LipE can afford increased opportunities for further elaboration to lead compounds in the hit-to-lead process.
The full definition of Lipophilic Ligand Efficiency is
LLE or LipE = pXC50 −log P (or log D7.4)
XC50 refers to the negative logarithm of the binding affinity in molar concentration, which can be measured as either EC50 or IC50. logD7.4 is log D at pH 7.4, the physiological pH of blood serum.
The EC50 is the concentration of a molecule that gives half-maximal response. The IC50 is the concentration of an inhibitor where the response (or binding) is reduced by half.