Computational approach to the basicity of a series of α1-adrenoceptor ligands in aqueous solution

In order to design any new potential drug, it is crucial to know their corresponding pK_a since their protonation state will be critical in the ligand-receptor interaction and it will play an essential role in their pharmacokinetic profile. Several authors have developed approaches for the computational determination of pK_a which involve the use of a thermodynamic cycle relating pK_a to the gas-phase proton basicity via the solvation energies of the products and the reactants. Such methods are very dependent on the solvation model used and the nature of the system. The theoretical pK_a of a number of agonists and antagonists of the α1A-adrenoceptor has been computed and the performance of this approach has been tested through comparison with the available and/or measured experimental pK_a values.