title: Molecular structure and pronounced conformational flexibility of doxorubicin in free and conjugated state within a drug-peptide compound.
abstract: The search for targeted drug delivery systems requires the design of drug-carrier complexes, which could both reach the malignant cells and preserve the therapeutic substance activity. A promising strategy aimed at enhancing the uptake and reducing the systemic toxicity is to bind covalently the drug to a cell-penetrating peptide. To understand the structure-activity relationship in such preparations, the chemotherapeutic drug doxorubicin was investigated by unrestrained molecular dynamics simulations, supported by NMR, which yielded its molecular geometry in aqueous environment. Furthermore, the structure and dynamics of a conjugate of the drug with a cell-penetrating peptide was obtained from molecular dynamics simulations in aqueous solution. The geometries of the unbound compounds were characterized at different temperatures, as well as the extent to which they change after covalent binding and whether/how they influence each other in the drug-peptide conjugate. The main structural fragments that affect the conformational ensemble of every molecule were found. The results show that the transitions between different substructures of the three compounds require a modest amount of energy. At increased temperature, either more conformations become populated as a result of the thermal fluctuations or the relative shares of the various conformers equalize at the nanosecond scale. These frequent structural interconversions suggest expressed conformational freedom of the molecules. Conjugation into the drug-peptide compound partially immobilizes the molecules of the parent compounds. Nevertheless, flexibility still exists, as well as an effective intra- and intermolecular hydrogen bonding that stabilizes the structures. We observe compact packing of the drug within the peptide that is also based on stacking interactions. All this outlines the drug-peptide conjugate as a prospective building block of a more complex drug-carrier system.
authors.affiliation: University of Sofia , Faculty of Chemistry and Pharmacy, Department of Physical Chemistry, 1 James Bourchier Avenue, 1164 Sofia, Bulgaria.
authors.forename: Yana
authors.initials: Y
authors.lastname: Tsoneva
authors.forename: Hendrik R A
authors.initials: HR
authors.lastname: Jonker
authors.forename: Manfred
authors.initials: M
authors.lastname: Wagner
authors.forename: Alia
authors.initials: A
authors.lastname: Tadjer
authors.forename: Marco
authors.initials: M
authors.lastname: Lelle
authors.forename: Kalina
authors.initials: K
authors.lastname: Peneva
authors.forename: Anela
authors.initials: A
authors.lastname: Ivanova
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000737:chemistry*; D002119:Calcium Carbonate; D002951:Citrates; D004317:Doxorubicin / Q000737:chemistry*; D004338:Drug Combinations; D008277:Magnesium Oxide; D009682:Magnetic Resonance Spectroscopy; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D011789:Quantum Theory; D013696:Temperature; D014867:Water / Q000737:chemistry
chemical_list: D000903:Antibiotics, Antineoplastic; D002951:Citrates; D004338:Drug Combinations; C050615:Suby's G solution; D014867:Water; D008277:Magnesium Oxide; D004317:Doxorubicin; D002119:Calcium Carbonate