Target recognition by DNA-binding ligands, such as drugs, occurs in an aqueous environment, in which water (near unit mole fraction, ~55 M) dominates every solute. A quantitative account of how water molecules are disposed in DNA/ligand binding is indispensable for understanding the driving forces that confer high-affinity and selectivity. We are investigating the DNA sequence selectivity of a model DNA minor groove-binding heterocyclic diamidine, DB1976, which shows therapeutic activity in acute myeloid leukemia, systemic fibroses, and obesity-related liver disorders in vivo. The DNA minor groove is richly populated with water molecules. Studies based on explicit-solvent MD simulation have shown distinct DNA dynamics upon drug-DNA complexes. We have cooperated the role of hydration and conformational dynamics in contributing to drug selectivity. Moving forward, our goal is to evaluate the structure-hydration relationships of designed diamidines to site-specific and nonspecific DNA as part of their biophysical characterization as potential therapeutic agents.