Computational approach to the basicity of a series of alpha1-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 alpha1A-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.