Structural and electronic determinants of flavonoid binding to human serum albumin: an extensive ligand-based study

Flavonoids are ubiquitous plant metabolites that interfere with different biological processes in the human organism. After absorption they bind to human serum albumin (HSA), the most abundant carrier protein in the blood which also binds various hormones and drugs. Binding of flavonoids to HSA may impact their distribution, influencing the active concentration in the blood. To determine the most prominent features responsible for binding of 20 different flavonoid aglycones to the IIA region of HSA, in vitro fluorescence measurements and density functional theory (DFT) calculations were conducted. These results were then integrated to elucidate structure-affinity relationships. The presented results reveal that flavones and flavonoles bind most strongly to the IIA region of HSA. There are several electronic and structural determinants associated with flavonoid binding to this HSA region: high C3 nucleophilicity and partial charge of O4, high HOMO and LUMO energies, and coplanarity of AC and B rings. Both steric and electronic characteristics of flavonoids have a great impact on their binding to HSA, with hydrogen donor and acceptor properties and coplanarity being the most prominent.