Investigating the Role of Noncovalent Interactions in Vadadustat's Solubility and Stability With Selected Solvents

ABSTRACT This study theoretically characterizes the noncovalent interactions between the drug Vadadustat (VD) and four common solvents: dimethyl formamide (DMF), dimethyl sulfoxide (DMSO), ethanol (EtOH), and water. Using Density Functional Theory (DFT) at the ωB97XD/cc‐pVDZ level, 12 distinct VD‐solvent systems were optimized to explicitly model solvation dynamics. The negative binding energies calculated for all systems confirm the thermodynamic favorability of complex formation. A multi‐tool protocol BerchNCI 1.0, which includes Natural Bond Orbital (NBO) analysis, Quantum Theory of Atoms in Molecules (QTAIM), Noncovalent Interaction (NCI) analysis, Interaction Region Indicator (IRI), and XEDA (energy decomposition analysis), was employed to provide a comprehensive understanding of the interactions. The results consistently indicate that VD forms the strongest interactions with DMSO, particularly in the VD‐DMSO‐C system, which showed the most negative binding energy (‐27.92 kcal/mol) and the highest stabilization energy in NBO analysis (34.02 kcal/mol). QTAIM analysis further supported this finding, identifying stronger hydrogen bonds in the VD‐DMSO‐C, VD‐EtOH‐C, and VD‐water‐A systems. The NCI and IRI analyses corroborate these findings, revealing stronger hydrogen bond regions for VD‐DMSO‐C, VD‐EtOH‐C, and VD‐water‐A. XEDA confirmed that attractive forces, primarily electrostatic and exchange components, dominate the interactions in all systems. This detailed molecular‐level investigation provides crucial insights into the stability, solubility, and bioavailability of VD. Future work will extend this analysis to mixed solvent environments and interactions with biological macromolecules to better predict drug behavior in a complex physiological milieu.