SAMPL7 blind challenge: quantum-mechanical prediction of partition coefficients and acid dissociation constants for small drug-like molecules

The physicochemical properties of a drug molecule determine the therapeutic effectiveness of the drug. Thus, the development of fast and accurate theoretical approaches for the prediction of such properties is inevitable. The participation to the SAMPL7 challenge is based on the estimation of logP coefficients and pK(a) values of small drug-like sulfonamide derivatives. Thereby, quantum mechanical calculations were carried out in order to calculate the free energy of solvation and the transfer energy of 22 drug-like compounds in different environments (water and n-octanol) by employing the SMD solvation model. For logP calculations, we studied eleven different methodologies to calculate the transfer free energies, the lowest RMSE value was obtained for the M06L/def2-TZVP//M06L/def2-SVP level of theory. On the other hand, we employed an isodesmic reaction scheme within the macro pK(a) framework; this was based on selecting reference molecules similar to the SAMPL7 challenge molecules. Consequently, highly well correlated pK(a) values were obtained with the M062X/6-311+G(2df,2p)//M052X/6-31+G(d,p) level of theory.

Automated summary

The physicochemical properties of a drug molecule play a crucial role in determining the therapeutic effectiveness of the drug. This study involved quantum mechanical calculations to predict solvation free energy and transfer energy of drug-like compounds, achieving high accuracy and correlation in logP and pK(a) value predictions.