22
M. P. Evstigneev and A. V. Shestopalova
2.1 Introduction
Rational design of new compounds for therapeutics requires knowledge about their
structural stability and interactions with various cellular macromolecules—their
molecular receptors or targets. In order to optimize the efficacy of drugs, as well
as discover new ones, it is important to fully characterize the drug—bioreceptor
(biopolymer) interaction [1].
Nucleic acids (NA) are common targets for antiviral, antibiotic and anticancer
drugs that are used in cancer therapeutics [2] and also are viewed as a non-specific
target for cytotoxic agents [3]. Many antitumour drugs are considered to exert their
cytotoxic effect through DNA-specific interactions, resulting in genotoxic stress and
consequent induction of programmed cell death (apoptosis) [4]. Presently, when
patients can be provided with a full genome sequence as a part of their medical
records, the field of drug design must be adapted and improved in order to meet this
challenge [5]. Rational drug design thus requires detailed knowledge of both the
structural consequences of ligation and the binding characteristics of the drug. Ideally, such information is required for DNA targets of genomic size and complexity [6].
In this regard it is important to know how small biologically active molecules—
drugs or other ligands—will interact with nucleic acids [7]. One can use biophysical
techniques to characterize the binding of the drugs with DNA and, based on experimental data, to expand further understanding of the binding process with an aid of
molecular modelling or computer simulations. Such approach allows to get different physical parameters of the interaction in the system “molecular target (DNA)—
drug” and to use them for the establishment of correlation between these parameters
and drug activity in vitro or in vivo [8, 9].
2.2 Biophysical Methods for Studying DNA-Drug
Complexation
One of extensively developing trends in molecular biophysics is prediction of pharmacological action of drugs at the molecular level that requires: (1) determination
of the structural features of the complexes “target-drug” containing the biologically
active ligands and exerting their maximal biological effectiveness; (2) determination of correlations of the physical parameters of interaction in the system “target-drug” and the biological activity of the drugs; (3) obtaining the most probable
molecular models of the “target-drug” complexes based on various experimental
physical methods and molecular modelling studies. As a practical outcome, one
can formulate recommendations for the synthesis of new biologically active ligands
with improved pharmacological properties based on information about the biomolecular target and the calculated physical parameters of ligand interaction with the
target.
M. P. Evstigneev and A. V. Shestopalova
2.1 Introduction
Rational design of new compounds for therapeutics requires knowledge about their
structural stability and interactions with various cellular macromolecules—their
molecular receptors or targets. In order to optimize the efficacy of drugs, as well
as discover new ones, it is important to fully characterize the drug—bioreceptor
(biopolymer) interaction [1].
Nucleic acids (NA) are common targets for antiviral, antibiotic and anticancer
drugs that are used in cancer therapeutics [2] and also are viewed as a non-specific
target for cytotoxic agents [3]. Many antitumour drugs are considered to exert their
cytotoxic effect through DNA-specific interactions, resulting in genotoxic stress and
consequent induction of programmed cell death (apoptosis) [4]. Presently, when
patients can be provided with a full genome sequence as a part of their medical
records, the field of drug design must be adapted and improved in order to meet this
challenge [5]. Rational drug design thus requires detailed knowledge of both the
structural consequences of ligation and the binding characteristics of the drug. Ideally, such information is required for DNA targets of genomic size and complexity [6].
In this regard it is important to know how small biologically active molecules—
drugs or other ligands—will interact with nucleic acids [7]. One can use biophysical
techniques to characterize the binding of the drugs with DNA and, based on experimental data, to expand further understanding of the binding process with an aid of
molecular modelling or computer simulations. Such approach allows to get different physical parameters of the interaction in the system “molecular target (DNA)—
drug” and to use them for the establishment of correlation between these parameters
and drug activity in vitro or in vivo [8, 9].
2.2 Biophysical Methods for Studying DNA-Drug
Complexation
One of extensively developing trends in molecular biophysics is prediction of pharmacological action of drugs at the molecular level that requires: (1) determination
of the structural features of the complexes “target-drug” containing the biologically
active ligands and exerting their maximal biological effectiveness; (2) determination of correlations of the physical parameters of interaction in the system “target-drug” and the biological activity of the drugs; (3) obtaining the most probable
molecular models of the “target-drug” complexes based on various experimental
physical methods and molecular modelling studies. As a practical outcome, one
can formulate recommendations for the synthesis of new biologically active ligands
with improved pharmacological properties based on information about the biomolecular target and the calculated physical parameters of ligand interaction with the
target.