COMPARISON OF METHODS TO ESTIMATE THE FREE-ENERGY OF SOLVATION - IMPORTANCE IN THE MODULATION OF THE AFFINITY OF 3-BENZAZEPINES FOR THE D1-RECEPTOR

We computed the free energy of solvation for a series of ions and neutral molecules using two different continuum approaches. First, we used the AMI-SM1 technique, where the AM1 Fock matrix is modified to include a generalized Born contribution. Second, we applied the DelPhi approach, where the electrostatic component of the free energy of solvation is evaluated by resolving the Poisson-Boltzman equation by a finite difference method. Both methods appear equally reliable for ionic systems. For neutral compounds, AM1-SM1 performs better than DelPhi; however, the differences become less pronounced for compounds with larger free energies of solvation. In parallel, both methods were applied to study the influence of the solvation process in the overall drug receptor interaction for a series of closely related ligands for the D1 dopamine receptor. An inverse linear relationship was found between the free energy of solvation and the logarithm of the affinity of the ligands; nevertheless, electrostatic properties are likely to modulate affinity as well.