The Average Electron Density Tool for Bioisosterism in Hydrophobic Media

Solvent effects influence the electronic properties of drug-like molecules, including their behavior in bioisosteric design. This study investigates the impact of hydrophobic environments, modeled using the solvation model based on density (SMD), on the average electron density (AED) values of 63 bioisosteric moieties of carboxylic acid. Dipole moments and AED values were computed at the B3LYP-D3-(BJ)/6-311++G-(d,p) level of theory, followed by atom in molecule analysis. The AED values remained consistent, irrespective of the dielectric constant of the hydrophobic medium. These findings support the applicability of the AED tool for evaluating bioisosterism even in nonpolar environments such as the interior of a protein. Furthermore, solvent-induced changes in AED were evaluated under polar and nonpolar solvation, using the SMD model versus the integral equation formalism polarizable continuum model (IEFPCM). Results show that both models yield comparable AED values and, thus, either is suitable for studying AED while accounting for solvent effects.