The solubility, lipophilicity and permeability of a drug ligand in cell membrane is governed by the pKa’s of the acidic and basic sites within the molecule. When the ligand is in the target protein environment, its affinity, activity and efficacy is dependent on the pKa’s of the interacting residues of the active site. In our lab different approaches for the evaluation of pKa’s are being tested.
-Relationship between experimental pKa’s, atomic charges and DFT descriptors: the linear relationship between atomic charges and experimental pKa’s depends on many factors: the choice of the DFT method, the choice of the basis set, the use (or not) of an implicit solvent model, the type and identity of the atomic charge model. Besides, DFT descriptors are evaluated by using the energetics of the Frontier orbitals as well as the charge distribution in the molecule. All these variables are being tested and correlated with the experimental pKa’s. The equations derived from these relationships are used for the exact determination of pKa’s of similar species.
-Usage of the isodesmic rections and the thermodynamic cycle for the evalution of pKa’s: Theoretical and quantitative prediction of pKa values at low computational cost is a current challenge in computational chemistry. Thermodynamic cycles are used for the prediction of pKavalues emphasizing their advantages and disadvantages. An alternative method for pKapredictions, which avoids gas phase calculations and related problems, is the isodesmic reaction. This method is currently used as it has been proven to provide very accurate pKa values for a variety of organic functionalities. The experimental part of this study is currently being carried out by Prof. Ilknur Doğan in Boğaziçi University.