27
including their complexes with ligands, and to determine the hydration properties
of the complexes being formed [54, 55, 83, 84].
Another very valuable tool in arsenal of theoretical investigation of biological
molecules is the method of molecular dynamics simulations. This computational
method describes the time dependent behaviour of the given molecular system. To
date an extensive use of molecular dynamics simulations has resulted in generation
of a wealth of detailed information on the fluctuations and conformational changes
of proteins and nucleic acids. Such methods are now routinely used to investigate
the structure, dynamics and thermodynamics of biological molecules and their complexes [48–50, 65–71, 85].
2.3 Results of Experimental Investigation and Computer
Simulation of DNA Complexation with New Synthetic
Analogues of Anticancer Antibiotics
2.3.1 General Description of New Synthetic Analogues
of Anticancer Antibiotics
As outlined above, in order to provide a scientific basis for rational design of DNAtargeted drugs, it is necessary to understand how the molecules form complexes
with DNA. Another important factor is the ability to quantify such complexation in
order to make meaningful comparisons of the behaviour of different drugs. This is
the focus of the biophysical studies reviewed below.
Here we present the results of investigations of the physical mechanisms of the
interaction with DNA of a new series of biologically-active ligands, analogues of
anticancer antibiotic Actinomycin D (AMD), obtained using complex approach involving various experimental biophysical methods and molecular computer modeling.
AMD, the synthetic phenoxazone antibiotic, consists of a phenoxazone chromophore substituted with two equivalent cyclic pentapeptide lactone rings. AMD is a
DNA-binding drug. Its biological activity is thought to be due to preferential intercalation of the planar phenoxazone chromophore into GC sequence of DNA with
the two cyclic pentapeptide rings lying in the minor groove [86].
AMD is an anticancer drug used in treatment of tumours, but its use suffers
from induction of negative side effects [87]. With a general aim to reduce the side
toxicity of AMD, a new set of drugs with phenoxazone chromophore and dimethylaminoalkyl side chains (actinocin derivatives with side chains of different lengths,
ActII—ActV, Fig. 2.1) have been synthesized [8].
The cytotoxic effects of the synthetic actinocin derivatives were investigated by
examination of the drug-induced apoptosis and cell cycle perturbations in a human
leukemia MOLT-3 cell line [88].
Examination of cytotoxic effects in leukemia cells showed that the variation in
length of dimethylaminoalkyl side chains of actinocin derivatives leads to signifi2 Structure, Thermodynamics and Energetics of Drug-DNA Interactions
including their complexes with ligands, and to determine the hydration properties
of the complexes being formed [54, 55, 83, 84].
Another very valuable tool in arsenal of theoretical investigation of biological
molecules is the method of molecular dynamics simulations. This computational
method describes the time dependent behaviour of the given molecular system. To
date an extensive use of molecular dynamics simulations has resulted in generation
of a wealth of detailed information on the fluctuations and conformational changes
of proteins and nucleic acids. Such methods are now routinely used to investigate
the structure, dynamics and thermodynamics of biological molecules and their complexes [48–50, 65–71, 85].
2.3 Results of Experimental Investigation and Computer
Simulation of DNA Complexation with New Synthetic
Analogues of Anticancer Antibiotics
2.3.1 General Description of New Synthetic Analogues
of Anticancer Antibiotics
As outlined above, in order to provide a scientific basis for rational design of DNAtargeted drugs, it is necessary to understand how the molecules form complexes
with DNA. Another important factor is the ability to quantify such complexation in
order to make meaningful comparisons of the behaviour of different drugs. This is
the focus of the biophysical studies reviewed below.
Here we present the results of investigations of the physical mechanisms of the
interaction with DNA of a new series of biologically-active ligands, analogues of
anticancer antibiotic Actinomycin D (AMD), obtained using complex approach involving various experimental biophysical methods and molecular computer modeling.
AMD, the synthetic phenoxazone antibiotic, consists of a phenoxazone chromophore substituted with two equivalent cyclic pentapeptide lactone rings. AMD is a
DNA-binding drug. Its biological activity is thought to be due to preferential intercalation of the planar phenoxazone chromophore into GC sequence of DNA with
the two cyclic pentapeptide rings lying in the minor groove [86].
AMD is an anticancer drug used in treatment of tumours, but its use suffers
from induction of negative side effects [87]. With a general aim to reduce the side
toxicity of AMD, a new set of drugs with phenoxazone chromophore and dimethylaminoalkyl side chains (actinocin derivatives with side chains of different lengths,
ActII—ActV, Fig. 2.1) have been synthesized [8].
The cytotoxic effects of the synthetic actinocin derivatives were investigated by
examination of the drug-induced apoptosis and cell cycle perturbations in a human
leukemia MOLT-3 cell line [88].
Examination of cytotoxic effects in leukemia cells showed that the variation in
length of dimethylaminoalkyl side chains of actinocin derivatives leads to signifi2 Structure, Thermodynamics and Energetics of Drug-DNA Interactions