32
M. P. Evstigneev and A. V. Shestopalova
and NH 2 (ND 2 ) groups of the drugs. These changes in spectral parameters confirm
simultaneous hydration of the drugs and DNA, which most likely originates from
the water molecules acting as bridges between the drugs and DNA. In the case of
actinocin derivative ActII there is also an interaction between cationic groups of the
drug and DNA sugar-phosphate backbone resulting in additional stabilization of the
DNA-ActII complex.
In order to determine the most probable molecular models of the hydrated actinocin drug-DNA complexes, computer simulations of the interaction of the drugs
and DNA fragments (referred to as “the target”) were carried out.
First, molecular docking methods were applied to the systems containing nucleic
acids fragments as the targets and actinocin derivatives with different lengths of the
dimethylaminoalkyl side chains as the ligands. It was found that the actinocin derivatives could form energetically favourable complexes with DNA both as intercalators and minor groove binders. The complexes of actinocin derivatives and DNA
fragments were stabilized by hydrogen bonding on either, intercalation and minor
groove binding. It was found that the change in solvent-accessible surface area on
binding of the actinocin derivatives with DNA linearly increases with the number
of CH 2 groups in the ligands’ side chains. The solvation energy change on binding,
calculated by the weighted solvent-accessible surface area method, was reported to
be unfavourable for positively charged ligands [92].
Second, the Monte Carlo method was employed taking the solvent (water molecules) into account [89]. The following assumptions were introduced as a result of
the experimental investigations of actinocin-DNA complexation reviewed above
and of the molecular docking simulations: (1) the possibility of intercalation of the
planar phenoxazone chromophore of actinocin drug into GC-sites of DNA, and
(2) the possibility of binding of the actinocin derivatives in the minor groove of
the double helix. Hence, the starting configurations of the complexes were built in
agreement with these assumptions. The energy parameters of the molecular systems
containing free DNA fragments and their complexes with various intercalated actinocin derivatives, and for the actinocin derivatives bound in the minor groove of
DNA fragments, were obtained. Using these data, some conclusions concerning the
stability of the molecular complexes could be made by comparison of the values
of the average total potential energies of the systems studied and the drug-target
interaction energy. For the series of actinocin drugs it was found that the highest by
absolute value target-drug interaction energy was associated specifically with the
ActII-target system for the both types of complexes.
Analysis of the instantaneous configurations of all the complexes had enabled us
to describe the obtained structures in more detail. A remarkable feature of the structure of the free ActII in solution is the presence of intramolecular hydrogen bond between C = O and N-H groups of one of the dimethylaminoalkyl chains [90], which
may hinder the conformational fitting of the side chain of the drug when interacting
with DNA. This intramolecular hydrogen bond is preserved on complexation of
ActII with the DNA fragment.
The complex of ActII with the DNA fragment is additionally stabilized by formation of two hydrogen bonds between O4′ atoms of the deoxyribose rings of both
chains and NH 2 -group of the drug chromophore and NH-group of one of the side
M. P. Evstigneev and A. V. Shestopalova
and NH 2 (ND 2 ) groups of the drugs. These changes in spectral parameters confirm
simultaneous hydration of the drugs and DNA, which most likely originates from
the water molecules acting as bridges between the drugs and DNA. In the case of
actinocin derivative ActII there is also an interaction between cationic groups of the
drug and DNA sugar-phosphate backbone resulting in additional stabilization of the
DNA-ActII complex.
In order to determine the most probable molecular models of the hydrated actinocin drug-DNA complexes, computer simulations of the interaction of the drugs
and DNA fragments (referred to as “the target”) were carried out.
First, molecular docking methods were applied to the systems containing nucleic
acids fragments as the targets and actinocin derivatives with different lengths of the
dimethylaminoalkyl side chains as the ligands. It was found that the actinocin derivatives could form energetically favourable complexes with DNA both as intercalators and minor groove binders. The complexes of actinocin derivatives and DNA
fragments were stabilized by hydrogen bonding on either, intercalation and minor
groove binding. It was found that the change in solvent-accessible surface area on
binding of the actinocin derivatives with DNA linearly increases with the number
of CH 2 groups in the ligands’ side chains. The solvation energy change on binding,
calculated by the weighted solvent-accessible surface area method, was reported to
be unfavourable for positively charged ligands [92].
Second, the Monte Carlo method was employed taking the solvent (water molecules) into account [89]. The following assumptions were introduced as a result of
the experimental investigations of actinocin-DNA complexation reviewed above
and of the molecular docking simulations: (1) the possibility of intercalation of the
planar phenoxazone chromophore of actinocin drug into GC-sites of DNA, and
(2) the possibility of binding of the actinocin derivatives in the minor groove of
the double helix. Hence, the starting configurations of the complexes were built in
agreement with these assumptions. The energy parameters of the molecular systems
containing free DNA fragments and their complexes with various intercalated actinocin derivatives, and for the actinocin derivatives bound in the minor groove of
DNA fragments, were obtained. Using these data, some conclusions concerning the
stability of the molecular complexes could be made by comparison of the values
of the average total potential energies of the systems studied and the drug-target
interaction energy. For the series of actinocin drugs it was found that the highest by
absolute value target-drug interaction energy was associated specifically with the
ActII-target system for the both types of complexes.
Analysis of the instantaneous configurations of all the complexes had enabled us
to describe the obtained structures in more detail. A remarkable feature of the structure of the free ActII in solution is the presence of intramolecular hydrogen bond between C = O and N-H groups of one of the dimethylaminoalkyl chains [90], which
may hinder the conformational fitting of the side chain of the drug when interacting
with DNA. This intramolecular hydrogen bond is preserved on complexation of
ActII with the DNA fragment.
The complex of ActII with the DNA fragment is additionally stabilized by formation of two hydrogen bonds between O4′ atoms of the deoxyribose rings of both
chains and NH 2 -group of the drug chromophore and NH-group of one of the side