The most commonly used measure of lipophilicity is LogP, this is the partition coefficient of a molecule between an aqueous and lipophilic phases, usually octanol and water. Measurement of LogP can be undertaken in a variety of ways, the most common is the shake-flask method, which consists of dissolving some of the solute in question in a volume of octanol and water, shaking for a period of time, then measuring the concentration of the solute in each solvent.
This can be time-consuming particularly if there is no quick spectroscopic method to measure the concentration of the molecule in the phases. A faster method of log P determination makes use of high-performance liquid chromatography. The log P of a solute can be determined by correlating its retention time with similar compounds with known log P value doi.
Many of these applications work by using a large training data-set of known values to determine fragment contributions for sub-structures and functional groups, however logP is not a simple additive property and correction terms are needed to allow for proximity effects, H-bonding, electronic effects etc.
For unknown functional groups the programs often approximate using individual atom contributions. Atomic e. Atomic logP considers that each atom has a contribution to the logP, and that the contributions to the final value is purely additive. However it is clear that a nitrogen in an amide is different to a nitrogen in an amine or pyridine, Enhanced Atomic takes into account the atom type.
Fragment methods use a large training data-set of known values to determine fragment contributions for sub-structures and functional groups, together with correction terms to account for proximity effects.
These methods often fall back on atomic models for novel functional groups. Property based methods tend to be computationally demanding and not really suitable for testing large datasets. Because the training sets and the algorithms vary between applications it is very important not to combine calculated results using different tools. Some of the tools allow the user to extend the training set using in house measured values, this may be critical when exploring novel functional groups or scaffolds.
However the majority of known drugs contain ionisable groups, as shown in the histogram below, this shows the distribution of small molecule drugs with DrugBank and are likely to be charged at physiological pH and LogP only correctly describes the partition coefficient of neutral uncharged molecules.
LogD the distribution constant is a better descriptor of the lipophilicity of a molecule. This can be determined in a similar manner to LogP but instead of using water, the aqueous phase is adjusted to a specific pH using a buffer.
Log D is thus pH dependent, hence the one must specify the pH at which the log D was measured. Applications like Marvin allow the user to calculate the logD but also display the pH distribution profile, as shown below for Warfarin. For compounds with a pKa close to physiological pH it may be critical to consider what might actually be the predominant ionised form. This can also be valuable when thinking about absorption from the different regions of the alimentary canal where the pH ranges from in the stomach to in the ileum.
LogD is more convenient for practical measurements, as it takes into account solution pH, which is important for the analysis of the drug candidate properties in various biologic media with different pH values. Incubations are done in duplicates. Other pH buffers and customized assay setups are available upon request.
Reliable measurable range is approximately -1 to 4. Note: Pricing for this service refers to logD determination at one selected pH. For non-charged compounds at the pH used for logD measurements logD equals logP, and there is no extra charge for logP measurement.
For compounds with known pKa values, price for logP determination will be equal to the price of logD determination; the same applies for the cases where in silico calculated pKa values are used. Pricing for the experimental pKa measurements is subject to discussion and depends on the properties of the tested compounds. Deliverable Calculations of the partition ratios peak area of the analyte in octanol phase to the peak area of the analyte in PBS buffer.
Full study report is provided.
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