47
interactions in solution for variety of aromatic molecules [116], largely resembling
the process of DNA intercalation.
Search of a correlation ( r) of the energy terms in Eq. (2.5) with the experimental
energy, ΔG exp , has shown that the highest impact on it is provided by the VDW
energy of ligand insertion, ∆G vdW
ins
( r = 0.66) and VDW energy of DNA unwinding,
∆G vdW
uw
( r = –0.67). The rest terms give lower correlation not exceeding |r| = 0.5. The
correlation between ΔG exp and ΔG hyd was equal to r = 0.42. This result is in accord
with the above-made conclusion on the importance of VDW interactions in the
net energetics of binding. Noteworthy, the EL energy, formally featuring the largest magnitude of the energy components (see Table 2.2), appears to be relatively
unimportant in the modulating the binding affinity in the intercalation reactions.
This result highlights the key role of the intermolecular VDW forces in managing
the affinity of aromatic drugs to DNA and points out the way to modify the ligand
structure with an aim to increase the binding strength with DNA.
2.4.4 Energy Analysis of DNA Minor Groove Binding Reactions
Ligand molecules which exert predominant affinity to DNA minor groove commonly contain a set of hetero-cycles linked by single bonds and closely matching the
shape of DNA minor groove. Typical examples of MGB-ligands are Hoechst33258,
Netropsin, Berenil, Distamycin. The DNA-binding and medico-biological properties of the MGB-ligands have been extensively reviewed and these molecules are
currently considered as promising agents in chemotherapy of cancer [127, 128].
The MGB-ligands exert major specificity to AT sites of DNA, covering approximately 4 base pairs when binding within the minor groove [127], hence, the nonselfcomplementary dodecamer d(CGCA 4 GCG)/(CGCT 4 GCG) may be selected as a
receptor in energy analysis [108].
The full energy analysis of MGB-ligands binding with DNA was accomplished
in Ref. [108] using the methodology generally similar to that reviewed above for
DNA intercalation. The general patterns of the sign and magnitude of various energy terms, already discussed above for DNA intercalators, were reported to be preserved in the case of MGB-binding as well. In particular, the compensatory effect,
the absence of apparent correlation of the net energies in Eq. (2.4) with the properties of ligand, and the coincidence of ΔG total and ΔG exp , remain valid. It was found
that there are at least three major stabilizing factors, appearing in Eq. (2.5), which
govern the binding process of the MGB-ligands with DNA, placed in descending
order according to the absolute value of the energy change: intermolecular electrostatic interactions ( ∆G el
im
), intermolecular van der Waals interactions (∆G vdW
im
) and
hydrophobic interactions (ΔG hyd ). The stabilization of the complexes is also provided by the formation of intermolecular H-bonds ( N
im
), formation of residual mechanical vibrations in the binding site (∆G v
II
) and the polyelectrolyte factor (ΔG pe )—the
latter two giving minor contribution as compared to other factors. The major factors
which destabilize complexes of the MGB-ligands with DNA are the electrostatic
2 Structure, Thermodynamics and Energetics of Drug-DNA Interactions
interactions in solution for variety of aromatic molecules [116], largely resembling
the process of DNA intercalation.
Search of a correlation ( r) of the energy terms in Eq. (2.5) with the experimental
energy, ΔG exp , has shown that the highest impact on it is provided by the VDW
energy of ligand insertion, ∆G vdW
ins
( r = 0.66) and VDW energy of DNA unwinding,
∆G vdW
uw
( r = –0.67). The rest terms give lower correlation not exceeding |r| = 0.5. The
correlation between ΔG exp and ΔG hyd was equal to r = 0.42. This result is in accord
with the above-made conclusion on the importance of VDW interactions in the
net energetics of binding. Noteworthy, the EL energy, formally featuring the largest magnitude of the energy components (see Table 2.2), appears to be relatively
unimportant in the modulating the binding affinity in the intercalation reactions.
This result highlights the key role of the intermolecular VDW forces in managing
the affinity of aromatic drugs to DNA and points out the way to modify the ligand
structure with an aim to increase the binding strength with DNA.
2.4.4 Energy Analysis of DNA Minor Groove Binding Reactions
Ligand molecules which exert predominant affinity to DNA minor groove commonly contain a set of hetero-cycles linked by single bonds and closely matching the
shape of DNA minor groove. Typical examples of MGB-ligands are Hoechst33258,
Netropsin, Berenil, Distamycin. The DNA-binding and medico-biological properties of the MGB-ligands have been extensively reviewed and these molecules are
currently considered as promising agents in chemotherapy of cancer [127, 128].
The MGB-ligands exert major specificity to AT sites of DNA, covering approximately 4 base pairs when binding within the minor groove [127], hence, the nonselfcomplementary dodecamer d(CGCA 4 GCG)/(CGCT 4 GCG) may be selected as a
receptor in energy analysis [108].
The full energy analysis of MGB-ligands binding with DNA was accomplished
in Ref. [108] using the methodology generally similar to that reviewed above for
DNA intercalation. The general patterns of the sign and magnitude of various energy terms, already discussed above for DNA intercalators, were reported to be preserved in the case of MGB-binding as well. In particular, the compensatory effect,
the absence of apparent correlation of the net energies in Eq. (2.4) with the properties of ligand, and the coincidence of ΔG total and ΔG exp , remain valid. It was found
that there are at least three major stabilizing factors, appearing in Eq. (2.5), which
govern the binding process of the MGB-ligands with DNA, placed in descending
order according to the absolute value of the energy change: intermolecular electrostatic interactions ( ∆G el
im
), intermolecular van der Waals interactions (∆G vdW
im
) and
hydrophobic interactions (ΔG hyd ). The stabilization of the complexes is also provided by the formation of intermolecular H-bonds ( N
im
), formation of residual mechanical vibrations in the binding site (∆G v
II
) and the polyelectrolyte factor (ΔG pe )—the
latter two giving minor contribution as compared to other factors. The major factors
which destabilize complexes of the MGB-ligands with DNA are the electrostatic
2 Structure, Thermodynamics and Energetics of Drug-DNA Interactions