198
M. Ilchenko and I. Dubey
8 Å. It was shown that 9-aminoacridines selectively bind to G-quadruplex sequence
between A and G-tetrads, involving significant π- π-interactions and several strong
hydrogen bonds. The specific interactions between different moieties of the ligands
to the DNA were shown to play a key role in governing the overall stabilities of G4
complexes. The ligands were found to induce different level of structural stabilization through intercalation. This unique property of altering structural stability is likely a contributing factor for affecting telomerase function and, subsequently, the observed differences in the anticancer activities between the studied 9-aminoacridines.
The molecular modelling studies on binding of novel dimethylamino-ethyl-acridine analogues to G-quadruplex DNA were described in [128]. The comparison
of force field and quantum polarized docking methods was performed. The docking study was conducted at three levels: (a) Glide XP [129] force field docking,
(b) Quantum Polarized Ligand Docking (QPLD) using Jaguar software [130] with
B3LYP density functional method and LACVP basis sets, and (c) QPLD docking
with B3LYP density function method and LACVP* basis sets. Ultimately, the results from each of these methods were compared and contrasted for obtaining useful
insights. Binding energies were calculated for a number of ligands to identify three
drug-like molecules for future optimization.
As we have already mentioned, “pure” quantum chemical methods are now in
common use when G4 ligand structure optimization is considered. It is of great importance for the subsequent modelling of ligand-quadruplex binding by any method,
including docking or MD simulations, and at the same time can provide an interesting information helping to understand experimental data. For example, our quantum
chemical study of the molecular structure of efficient telomerase inhibitors, cationic
porphyrin-imidazophenazine conjugates and their metal complexes [131] supplemented and explained spectral data. Calculations were performed by DFT method
using M06 and M06-2X [88, 132] functionals that are known to adequately describe
stacking interactions, and 6-31G(d) and 6-31G(d, p) basic sets. Full geometry optimization was performed in vacuum and in water, employing the supermolecular
approximation and CPCM model [133] to consider the solvent effects. Calculations
demonstrated that conjugates could form stable intramolecular complexes due to
either stacking interaction or metal coordination between the chromophores. Both
in vacuum and water, two types of complexes are formed. Non-metalated conjugate
was found to adopt the conformation with coplanar chromophores stabilized by
π-π-stacking. At the same time, a hybrid containing Zn(II) porphyrin complex forms
different structure where the metal ion coordinates a nitrogen atom of Imidazophenazine fragment. The folding of linear conjugates to form intramolecular complexes
is energetically very favourable; e.g., for Zn(II) complex ΔG
298
of the process in
vacuum and water is 15.61 and 12.34 kcal/mol, respectively. The computation results fully confirmed the experimental data obtained for these conjugates and their
interaction with Tel22 G-quadruplex [134, 135]. The absorption and fluorescence
studies of the hybrids revealed the formation of intramolecular heterodimers based
on strong electronic interaction between the cationic porphyrin and imidazophenazine heterocycle, which obviously affects the binding of these telomerase inhibitors to intramolecular G4.
M. Ilchenko and I. Dubey
8 Å. It was shown that 9-aminoacridines selectively bind to G-quadruplex sequence
between A and G-tetrads, involving significant π- π-interactions and several strong
hydrogen bonds. The specific interactions between different moieties of the ligands
to the DNA were shown to play a key role in governing the overall stabilities of G4
complexes. The ligands were found to induce different level of structural stabilization through intercalation. This unique property of altering structural stability is likely a contributing factor for affecting telomerase function and, subsequently, the observed differences in the anticancer activities between the studied 9-aminoacridines.
The molecular modelling studies on binding of novel dimethylamino-ethyl-acridine analogues to G-quadruplex DNA were described in [128]. The comparison
of force field and quantum polarized docking methods was performed. The docking study was conducted at three levels: (a) Glide XP [129] force field docking,
(b) Quantum Polarized Ligand Docking (QPLD) using Jaguar software [130] with
B3LYP density functional method and LACVP basis sets, and (c) QPLD docking
with B3LYP density function method and LACVP* basis sets. Ultimately, the results from each of these methods were compared and contrasted for obtaining useful
insights. Binding energies were calculated for a number of ligands to identify three
drug-like molecules for future optimization.
As we have already mentioned, “pure” quantum chemical methods are now in
common use when G4 ligand structure optimization is considered. It is of great importance for the subsequent modelling of ligand-quadruplex binding by any method,
including docking or MD simulations, and at the same time can provide an interesting information helping to understand experimental data. For example, our quantum
chemical study of the molecular structure of efficient telomerase inhibitors, cationic
porphyrin-imidazophenazine conjugates and their metal complexes [131] supplemented and explained spectral data. Calculations were performed by DFT method
using M06 and M06-2X [88, 132] functionals that are known to adequately describe
stacking interactions, and 6-31G(d) and 6-31G(d, p) basic sets. Full geometry optimization was performed in vacuum and in water, employing the supermolecular
approximation and CPCM model [133] to consider the solvent effects. Calculations
demonstrated that conjugates could form stable intramolecular complexes due to
either stacking interaction or metal coordination between the chromophores. Both
in vacuum and water, two types of complexes are formed. Non-metalated conjugate
was found to adopt the conformation with coplanar chromophores stabilized by
π-π-stacking. At the same time, a hybrid containing Zn(II) porphyrin complex forms
different structure where the metal ion coordinates a nitrogen atom of Imidazophenazine fragment. The folding of linear conjugates to form intramolecular complexes
is energetically very favourable; e.g., for Zn(II) complex ΔG
298
of the process in
vacuum and water is 15.61 and 12.34 kcal/mol, respectively. The computation results fully confirmed the experimental data obtained for these conjugates and their
interaction with Tel22 G-quadruplex [134, 135]. The absorption and fluorescence
studies of the hybrids revealed the formation of intramolecular heterodimers based
on strong electronic interaction between the cationic porphyrin and imidazophenazine heterocycle, which obviously affects the binding of these telomerase inhibitors to intramolecular G4.