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 pKa 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 pKa which involve the use of a thermodynamic cycle relating pKa 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 pKa 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 pKa values.

The figure illustrates some of the α1-adrenoceptor ligands object of this study. Their pKa has been theoretically computed at B3LYP/6-31G∗ level and the experimental pKa for some of them has been measured by us.Figure optionsDownload as PowerPoint slide