29
with heterocyclic planar rings (aromatic ligands) in water are interesting from the
physico-chemical point of view, resulting in determination of the influence of the
structures of the chromophores and side chains on association ability, and estimation of contributions of different interactions to the formation of stable aggregates.
Another important issue is the pharmacological aspect, because the self- and heterocomplexations, as well as competitive binding of the drugs with bioreceptor, may
influence their activity.
Distinctive features of the self-association of the actinocin derivatives were
determined experimentally (by UV-VIS spectrophotometry, piezogravimetry and IRspectroscopy) and using computer simulation (by Monte Carlo method and molecular
dynamics modeling).
Analysis of both spectral and thermodynamic parameters obtained from UVVIS spectrophotometric data for the set of synthetic actinocin derivatives enabled
us to conclude that the drugs experience strong tendency to aggregate in solution
and the aggregation is appreciably higher in solutions of high ionic strength. The
dimerization parameters depend slightly on the number of methylene groups in the
side chains of phenoxazone antibiotics. Dimerization of the investigated ligands in
aqueous solution leads to significant changes in the spectral characteristics of the
antibiotics ActII-ActV, which needs to be taken into account in any studies of drug
complexation with DNA [89].
Formation of DNA complexes with actinocin derivatives is accompanied by hydration changes for both the DNA molecule and the intercalated ligands. In order to
evaluate the energy contribution of water molecules to stabilization of these complexes, it is necessary to obtain experimental data on the energies of interaction
between water molecules and the free ligands. An investigation of the adsorption
of water in the films of actinocin derivatives was performed using quartz crystal
microbalance (piezogravimetry). In order to identify the hydration-active centers,
the IR absorption spectra of wet and dry films of the actinocin derivatives were
recorded in the spectral range 900–1700 cm
−1
, in which the DNA molecules can be
characterized by the nitrogen base absorption region (1500–1700 cm
−1
) and by the
region of sugar phosphate absorption (900–1300 cm
−1
). The main conclusion of this
stage of investigation was that in contrast to the DNA molecule, the investigated
actinocin derivatives demonstrate very weak absorption in the spectral region 950–
1250 cm
−1
and, thereby, analysis of the IR spectra of the DNA-drug complexes can
be carried out without taking into account the drug absorption in this IR region [55].
Computer simulation of the hydrated environment of actinocin derivatives in
aqueous clusters by Monte Carlo method allows to determine the most energetically
favourable “ligand-water” configurations, the number and the positions of water
molecules forming hydrogen bonds with actinocin derivatives or their hydrated active sites. Comparative analysis of the simulation data and the results of IR-spectroscopic and piezogravimetric studies of the actinocin derivatives’ hydration had
demonstrated their complementarity and general agreement.
With an aim to investigate the molecular mechanisms of actinocin derivatives
complexation in water solution, the molecular dynamics simulation of both monomer and dimer forms of the ligands was carried out [90]. The hydration properties
2 Structure, Thermodynamics and Energetics of Drug-DNA Interactions
with heterocyclic planar rings (aromatic ligands) in water are interesting from the
physico-chemical point of view, resulting in determination of the influence of the
structures of the chromophores and side chains on association ability, and estimation of contributions of different interactions to the formation of stable aggregates.
Another important issue is the pharmacological aspect, because the self- and heterocomplexations, as well as competitive binding of the drugs with bioreceptor, may
influence their activity.
Distinctive features of the self-association of the actinocin derivatives were
determined experimentally (by UV-VIS spectrophotometry, piezogravimetry and IRspectroscopy) and using computer simulation (by Monte Carlo method and molecular
dynamics modeling).
Analysis of both spectral and thermodynamic parameters obtained from UVVIS spectrophotometric data for the set of synthetic actinocin derivatives enabled
us to conclude that the drugs experience strong tendency to aggregate in solution
and the aggregation is appreciably higher in solutions of high ionic strength. The
dimerization parameters depend slightly on the number of methylene groups in the
side chains of phenoxazone antibiotics. Dimerization of the investigated ligands in
aqueous solution leads to significant changes in the spectral characteristics of the
antibiotics ActII-ActV, which needs to be taken into account in any studies of drug
complexation with DNA [89].
Formation of DNA complexes with actinocin derivatives is accompanied by hydration changes for both the DNA molecule and the intercalated ligands. In order to
evaluate the energy contribution of water molecules to stabilization of these complexes, it is necessary to obtain experimental data on the energies of interaction
between water molecules and the free ligands. An investigation of the adsorption
of water in the films of actinocin derivatives was performed using quartz crystal
microbalance (piezogravimetry). In order to identify the hydration-active centers,
the IR absorption spectra of wet and dry films of the actinocin derivatives were
recorded in the spectral range 900–1700 cm
−1
, in which the DNA molecules can be
characterized by the nitrogen base absorption region (1500–1700 cm
−1
) and by the
region of sugar phosphate absorption (900–1300 cm
−1
). The main conclusion of this
stage of investigation was that in contrast to the DNA molecule, the investigated
actinocin derivatives demonstrate very weak absorption in the spectral region 950–
1250 cm
−1
and, thereby, analysis of the IR spectra of the DNA-drug complexes can
be carried out without taking into account the drug absorption in this IR region [55].
Computer simulation of the hydrated environment of actinocin derivatives in
aqueous clusters by Monte Carlo method allows to determine the most energetically
favourable “ligand-water” configurations, the number and the positions of water
molecules forming hydrogen bonds with actinocin derivatives or their hydrated active sites. Comparative analysis of the simulation data and the results of IR-spectroscopic and piezogravimetric studies of the actinocin derivatives’ hydration had
demonstrated their complementarity and general agreement.
With an aim to investigate the molecular mechanisms of actinocin derivatives
complexation in water solution, the molecular dynamics simulation of both monomer and dimer forms of the ligands was carried out [90]. The hydration properties
2 Structure, Thermodynamics and Energetics of Drug-DNA Interactions