Photophysical properties, topology, and Hirshfeld surface analysis of hydroxyurea and its molecular docking with caffeine and lactic acid: A potential drug for sickle cell disease

Hydroxyurea (HU) is widely prescribed for treating sickle cell disease, but its therapeutic effectiveness depends on solvent polarity and interactions with other drugs. Geometry optimization at B3LYP/6-31++G(d,p) shows that water causes structural changes and dihedral angle shifts due to hydrogen bonding. The FTIR shifts and thermodynamic data confirmed stronger solute–solvent interactions and increased stability in polar solvents. The HOMO–LUMO gap decreases from 7.59 eV in water to 7.11 eV in heptane, reflecting higher reactivity in nonpolar media. Chemical reactivity descriptors revealed that HU is more electrophilic and softer in polar environments. Density of states and electrostatic potential analyses revealed increased orbital delocalization, charge separation, and hydrogen bonding potential in water. Topological analyses highlight strong electron localization near O and N atoms with enhanced delocalization in aqueous media. Hirshfeld surface analysis confirmed that extensive hydrogen bonding networks in water were absent in the gas phase. Molecular docking indicated moderate binding affinities (−3.2 to −3.7 kcal/mol), which were strongest against protein 5e6e via stable hydrogen bonds and hydrophobic contacts. The docking affinity is −6.3 kcal/mol, suggesting that a synergistic effect could enhance its therapeutic efficacy.