clogP / clogD [Partition co-efficient / Distribution co-efficient [Measure of lipophilicity of a compound]

What information should we expect from cLog P values?

Will the test compound bind to a target protein? Will the test compound reach the destination by crossing lipid membranes? Will the test compound get stuck in the lipid bilayer?

Lipophilicity plays an important role in solubility, absorption, membrane penetration, plasma protein binding, distribution, In Vitro / In Vivo Assessment of ADME and PK Properties During Lead Selection / Optimization, CNS penetration and partitioning into other tissues or organs such as the liver and has an impact on the routes of clearance. It is important in ligand recognition, not only to the target protein but also CYP450 interactions, HERG binding.

clogP:  Everyone is aware that logP is the logarithm of partition coefficient of a compound between n-octanol and water. 

i.e. log(concentration of the compound in n-octanol / concentration of compound in water).

Any compound in medicinal chemistry project should have certain hydrophilicity for absorption or permeation.  logP value gives us an estimation of this property.  According to Lipinski, if a compounds logP is less than 5, such compounds absorption and permeation should be good. 

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if logP value is more - compound is hydrophobic and if logP value is less - compound is hydrophilic.

For comparison purpose, say if clogP of compounds X and Y are 2 and 4 respectively that means compound X is more hydrophilic than compound Y. 

On the same note, for example, if logP of a compound is 3.  That means, that compound is 1000 times more soluble in n-octanol than water.   _______________________________________________________________________________   

Note:  Most of the time the logP values we get to look in the journal articles or in the in-house medicinal chemistry programs are calculated and not experimental numbers.                                                     

Therefore, 'c' in clogP stands for 'calculated'.

 Note:  logP does not consider ionization of the molecules.  logP value can be used when the compounds under study are neutral molecules which are non-ionizable (non-ionized compounds), however in most of the drug discovery programs we deal with ionizable compounds.  Therefore, logP values for lipophilicity identification might not be a correct method. 

Note:  logD which is the measure of distribution co-efficient (similar to partition co-efficient) takes both ionized and un-ionized forms of the compound into consideration.  (a) Depending on pH, the ratio of ionized/un-ionized form of compound would change.  (b) Therefore, when log D values are provided, always pH at which the measurement was performed should be indicated. Typically the most interesting is pH 7.4, since the majority of known drugs contains ionizable groups and are likely to be charged at physiological pH.

logD = 0 - 3 (considered as optimal range for lipophilicity) -  Compounds with logD value between 0 - 3 tend to have good solubility and permeability [most favourable for oral absorption and cell membrane permeation]

 logD ~ 2 [for CNS projects] - most favourable for blood brain barrier permeation.

 logD < 0 [highly hydrophilic] and logD > 5 [highly lipophilic].

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In general, LC/MS/MS measurement is the choice for analysis.  Lipophilicity of compounds is assessed using the golden standard “shake-flask” method. The compound is dissolved in a solution with equal amounts of octanol and water, shaken for 3 hours, and then measured for the amount of compound in each phase. Log D values are calculated by the log ([compound]octanol / [compound]buffer).

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