title: Antibiotic doxorubicin and its derivative bind milk β-lactoglobulin.
abstract: β-Lactoglobulin (β-LG) is a member of lipocalin superfamily of transporters for small hydrophobic molecules such as doxorubicin and its derivatives. We located the binding sites of doxorubicin (DOX) and N-(trifluoroacetyl) doxorubicin (FDOX) with β-lactoglobulin in aqueous solution at physiological conditions, using FTIR, CD and fluorescence spectroscopic methods as well as molecular modeling. Structural analysis showed that DOX and FDOX bind β-LG via both hydrophilic and hydrophobic contacts with overall binding constants of K(DOX-)(β)(-LG)=1.0 (± 0.4)× 10(4)M(-1) and K(FDOX-)(β)(-LG)=2.5 (± 0.5)× 10(4)M(-1) and the number of drug molecules bound per protein (n) 1.2 for DOX and 0.6 for FDOX. Molecular modeling showed the participation of several amino acids in the drug-protein complexes with the free binding energy of -8.12 kcal/mol for DOX-β-LG and -7.74 kcal/mol for FDOX-β-LG complexes. DOX and FDOX do not share similar binding sites with β-LG. Protein conformation showed minor alterations with reduction of β-sheet from 58% (free protein) to 57-51% in the drug-β-LG complexes. β-LG can transport doxorubicin and its derivative in vitro.
authors.affiliation: Département de Chimie-Biologie, Université du Québec à Trois-Rivières, C.P. 500, Trois-Rivières, Québec, Canada.
authors.forename: Daniel
authors.initials: D
authors.lastname: Agudelo
authors.forename: Marc
authors.initials: M
authors.lastname: Beauregard
authors.forename: Gervais
authors.initials: G
authors.lastname: Bérubé
authors.forename: Heidar-Ali
authors.initials: HA
authors.lastname: Tajmir-Riahi
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000378:metabolism*; D004317:Doxorubicin / Q000737:chemistry* / Q000378:metabolism*; D007782:Lactoglobulins / Q000737:chemistry / Q000378:metabolism*; D008892:Milk / Q000737:chemistry*; D062105:Molecular Docking Simulation; D011485:Protein Binding; D055550:Protein Stability; D017433:Protein Structure, Secondary
chemical_list: D000900:Anti-Bacterial Agents; D007782:Lactoglobulins; D004317:Doxorubicin