Molecular Modeling to Estimate the Diffusion Coefficients of Drugs and Other Small Molecules

Diffusion is a spontaneous process and one of the physicochemical phenomena responsible for molecular transport, the rate of which is governed mainly by the diffusion coefficient; however, few coefficients are available because the measurement of diffusion rates is not straightforward. The translational diffusion coefficient is related by the Stokes-Einstein equation to the approximate radius of the diffusing molecule. Therefore, the stable conformations of small molecules were first calculated by molecular modeling. A simple radius r_s and an effective radius r_e were then proposed and estimated using the stable conformers with the van der Waals radii of atoms. The diffusion coefficients were finally calculated with the Stokes-Einstein equation. The results showed that, for the molecules with strong hydration ability, the diffusion coefficients are best given by r_e and for other compounds, r_s provided the best coefficients, with a reasonably small deviation of ~0.3 × 10^-6 cm²/s from the experimental data. This demonstrates the effectiveness of the theoretical estimation approach, suggesting that diffusion coefficients have potential use as an additional molecular property in drug screening.