Deoxyribonucleic acid (DNA) serves as a repository of genetic information in cells and is a critical molecular target for various antibiotics and anticancer drugs. A profound understanding of small molecule interaction with DNA is crucial for the rational design of DNA-targeted therapies. While the molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) and molecular mechanics/generalized Born surface area (MM/GBSA) approaches have been well established for predicting protein-ligand binding, their application to DNA-ligand interactions has been less explored. In this study, we systematically investigated the binding of 13 diverse small molecules to DNA, evaluating the accuracy of DNA-ligand interaction predictions across different solvation approaches, interior dielectric constants (ε