Lipophilic efficiency (LiPE), sometimes referred to as ligand-lipophilicity efficiency (LLE) is a parameter used in

drug design Drug design, often referred to as rational drug design or simply rational design, is the inventive process of finding new medications based on the knowledge of a biological target. The drug is most commonly an organic small molecule that acti ...

and

drug discovery In the fields of medicine, biotechnology and pharmacology, drug discovery is the process by which new candidate medications are discovered. Historically, drugs were discovered by identifying the active ingredient from traditional remedies or b ...

to evaluate the quality of research compounds, linking potency and

lipophilicity Lipophilicity (from Greek λίπος "fat" and φίλος "friendly"), refers to the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. Such non-polar solvents are themselves lip ...

in an attempt to estimate druglikeness. For a given compound LiPE is defined as the pIC₅₀ (or pEC₅₀) of interest minus the LogP of the compound. :

\ce = \ce - \log P

In practice, calculated values such as cLogP or calculated LogD are often used instead of the measured LogP or LogD. LiPE is used to compare compounds of different potencies (pIC₅₀s) and lipophilicities (LogP). High potency (high value of pIC₅₀) is a desirable attribute in drug candidates, as it reduces the risk of non-specific, off-target pharmacology at a given concentration. When associated with low clearance, high potency also allows for low total dose, which lowers the risk of

idiosyncratic drug reaction Idiosyncratic drug reactions, also known as type B reactions, are drug reactions that occur rarely and unpredictably amongst the population. This is not to be mistaken with idiopathic, which implies that the cause is not known. They frequently o ...

. On the other hand, LogP is an estimate of a compound's overall lipophilicity, a value that influence its behavior in a range of biological processes relevant to a drug discovery, such as solubility, permeability through biological membranes, hepatic clearance, lack of selectivity and non-specific toxicity. For oral drugs, a LogP value comprised between 2 and 3 is often considered optimal to achieve a compromise between permeability and first-pass clearance. LiPE allows capturing both values in a single parameter, and empirical evidence suggest that quality drug candidates have a high LiPE (>6); this value corresponds to a compound with a pIC₅₀ of 8 and a LogP of 2. Plotting LogP against pIC₅₀ for a range of compounds allows ranking series and individual compounds. An alternative equation uses the logarithm of the ratio of potency (measured as binding energy) and the partition coefficient to compute a lipophilic

ligand efficiency Ligand efficiency is a measurement of the binding energy per atom of a ligand to its binding partner, such as a receptor or enzyme. Ligand efficiency is used in drug discovery research programs to assist in narrowing focus to lead compounds with o ...

index (LE) with a different scale. :

\ce = \log\left(\frac\right)

The following review discusses LipE in the context of other compound efficiency metrics.

References

{{Medicinal chemistry Drug discovery Pharmacokinetics Medicinal chemistry