35
gen bond connects N-Н group of ActII with C = O group of ActII (intramolecular
hydrogen bond) or with the atom O4′ of the sugar-phosphate backbone of the DNA
fragment (intermolecular hydrogen bond). The formation of these hydrogen bonds
can explains the specificity of ActII interaction with GC-site of the DNA fragment.
Of special interest are the results of analysis of re-construction of the hydration environment in the process of complexes formation. The complexation of the
ligands with DNA is accompanied by partial or full dehydration of the ligand molecules and re-construction of DNA hydration shells. In the isolated state ActII forms
hydrogen bonds with 7 water molecules [90]. Ligand molecule was found to be
partially dehydrated in the intercalated state in GC-site. ActII preserves hydrogen
bonds with 3 water molecules. Two of these molecules occupy bridging positions
between HN and C = O groups of ActII and N3 atom of guanine, and C = O group
of ActII and NH group of guanine of the opposite strand.
2.3.4 Summary of the Results
It was found that at least two types of complexes may be formed between DNA and
actinocin derivatives, viz. the intercalation of planar phenoxazone chromophore of
the drugs into GC-sites of DNA double helix, and the binding of the drugs with the
minor groove of DNA duplex. The complex in minor groove is energetically less favourable than the intercalated one. A preference is observed for both the intercalated
and groove-bound types of complexes for the complexation of ActII with the DNA
target. Additional stabilization of the intercalated complex may be due to formation
of hydrogen bonds between the NH-group of dimethylaminoalkyl side chains of
ActII and the sugar-phosphate backbone of DNA, as well as formation of specific
water structure around this complex. It is likely that water molecules occupy bridging positions between the hydration-active centers of the drugs and DNA providing
additional stabilization to the intercalated type of complex.
In conclusion, it is worth noting that the biophysical investigation sketched out
above, including the set of experimental and computer simulations methods, has
enabled us to shed new light on the molecular mechanism of biological action of a
new series of biologically active ligands—analogues of anticancer antibiotic Actinomycin D. These data are in general agreement with the results of examination of
cytotoxic effects of the same set of drugs on cellular level [8].
2.4 Energetics of Drug Complexation with Nucleic Acids
2.4.1 The Problem Behind the Thermodynamic Analysis
Investigation of the structure and thermodynamics of drug binding with nucleic acids performed above, demonstrates the power of using various biophysical methods
2 Structure, Thermodynamics and Energetics of Drug-DNA Interactions
gen bond connects N-Н group of ActII with C = O group of ActII (intramolecular
hydrogen bond) or with the atom O4′ of the sugar-phosphate backbone of the DNA
fragment (intermolecular hydrogen bond). The formation of these hydrogen bonds
can explains the specificity of ActII interaction with GC-site of the DNA fragment.
Of special interest are the results of analysis of re-construction of the hydration environment in the process of complexes formation. The complexation of the
ligands with DNA is accompanied by partial or full dehydration of the ligand molecules and re-construction of DNA hydration shells. In the isolated state ActII forms
hydrogen bonds with 7 water molecules [90]. Ligand molecule was found to be
partially dehydrated in the intercalated state in GC-site. ActII preserves hydrogen
bonds with 3 water molecules. Two of these molecules occupy bridging positions
between HN and C = O groups of ActII and N3 atom of guanine, and C = O group
of ActII and NH group of guanine of the opposite strand.
2.3.4 Summary of the Results
It was found that at least two types of complexes may be formed between DNA and
actinocin derivatives, viz. the intercalation of planar phenoxazone chromophore of
the drugs into GC-sites of DNA double helix, and the binding of the drugs with the
minor groove of DNA duplex. The complex in minor groove is energetically less favourable than the intercalated one. A preference is observed for both the intercalated
and groove-bound types of complexes for the complexation of ActII with the DNA
target. Additional stabilization of the intercalated complex may be due to formation
of hydrogen bonds between the NH-group of dimethylaminoalkyl side chains of
ActII and the sugar-phosphate backbone of DNA, as well as formation of specific
water structure around this complex. It is likely that water molecules occupy bridging positions between the hydration-active centers of the drugs and DNA providing
additional stabilization to the intercalated type of complex.
In conclusion, it is worth noting that the biophysical investigation sketched out
above, including the set of experimental and computer simulations methods, has
enabled us to shed new light on the molecular mechanism of biological action of a
new series of biologically active ligands—analogues of anticancer antibiotic Actinomycin D. These data are in general agreement with the results of examination of
cytotoxic effects of the same set of drugs on cellular level [8].
2.4 Energetics of Drug Complexation with Nucleic Acids
2.4.1 The Problem Behind the Thermodynamic Analysis
Investigation of the structure and thermodynamics of drug binding with nucleic acids performed above, demonstrates the power of using various biophysical methods
2 Structure, Thermodynamics and Energetics of Drug-DNA Interactions