ACD/Method Development Suite

Determination of LogD and LogP Values Using ACD/Method Development Suite

Determine logD and logP values using experimental HPLC retention times and ACD/Method Development Suite. Increased compound lipophilicity is important for ADME because it correlates with poor solubility, increased metabolism, clearance, and volume of distribution. Therefore, a method that quickly gives accurate logP and logD values would be useful for high-throughput drug discovery.

This technique uses coordination of three different ACD/Labs modules: ChromManager, LC Simulator, and LogP DB. To use this feature, you need experimental logD values for a set of standard compounds. LogP and logD correlate well with logk'_w. If your HPLC method follows a primarily hydrophobic retention mechanism, you can use these standards for a wide range of test compounds. For more general HPLC methods, it is better to use standards that have similar functionality to your test compounds.

To develop a good equation, it is best to have at least five compounds and separate them using one or more different isocratic experiments. Import the chromatograms into ACD/ChromManager and peak-pick each component. Attach structures to relevant peaks using ACD/ChemSketch. ACD/LC Simulator combines the chromatograms, extrapolates to 0% organic, and generates a prediction equation using experimental logP/D. Copy the prediction equation to the chromatogram and ACD/ChromManager retains the prediction equation with the saved or stored chromatogram.

Calculate logP/logD based on k'_w for new compounds using the predicted k'_w-logP/logD equation and transfer logP/logD values to the ACD/LogP User Database using ACD/ChromManager.

From the ACD/Labs menu, choose LogP DB and open the user database. LogP DB will prompt you to overwrite the values for each of the structures; you should accept only the new structures. Transform retention times into logP/logD values and transfer them into an ACD/LogP DB training database. Users must have ACD/LogD Suite installed on their computer to be able to put both logD and logP values into a User Database.

You now have extracted experimental values for one or more new structures. These will be used to increase the accuracy of calculations of logP, logD, and solubility values for new compounds.

This technique meets the demand for accurate determination of lipophilicity values and facilitates high-throughput screening of drug-like molecules, using common HPLC.

See also:
The application note Determining LogD Values From Chromatographic Experiments
(PDF, 129 Kb).