Structure, Thermodynamics and Energetics of Drug-DNA Interactions: Computer Modeling and Experiment

Abstract

In this chapter we demonstrate the large usefulness of using complex approach for understanding the mechanism of binding of biologically active compounds (antitumour antibiotics, mutagens etc.) with nucleic acids (NA). The applications of various biophysical methods and computer modeling to determination of structural (Infra-red and Raman vibrational spectroscopies, computer modeling by means of Monte-Carlo, molecular docking and molecular dynamics methods) and thermodynamic (UV-VIS spectrophotometry, microcalorimetry, molecular dynamics simulation) parameters of NA-ligand complexation with estimation of the role of water environment in this process, are discussed. The strategy of energy analysis of the NA-ligand binding reactions in solution is described, which is based on decomposition of experimentally measured net Gibbs free energy of binding in terms of separate energetic contributions from particular physical factors. The main outcome of such analysis is to answer the questions "What physical factors and to what extent stabilize/destabilize NA-ligand complexes?" and "What physical factors most strongly affect the bioreceptor binding affinity?"

The theory of interceptor-protector action of DNA binding drugs

“…Such molecules feature strong p-stacking interactions with each other which is considered to be the principal driving force stabilizing intercalated complexes of aromatic drugs with DNA (Evstigneev, 2010;Kostjukov et al, 2009;Evstigneev and Shestopalova, 2014), as well as drug-interceptor hetero-complexes (Borowik et al, 2018;Larsen et al, 1996;Kostjukov et al, 2011;Evstigneev, 2014). This property allows one to predict the biological interaction for other drugs' combinations.…”

The energetics of small molecules binding with nucleic acids

“…It has long been recognized that experimentally measured thermodynamic parameters, DG, DH, DS and DC p , are made up of the sum of contributions from various types of physical interactions (see Refs. [14,15] and references therein), viz. van der Waals, electrostatic, hydrophobic etc:…”

“…the complexation constant or biological activity)'. It was proposed [14,25,26] that these principal tasks of energy analysis can be solved, if a protocol for computation of the contributions to the energies of the principal energy terms (or parsing/decomposition of the Gibbs energy) satisfies the following conditions:…”

“…the ligand dimensions, type of side chains and electric charge [25,26,88]. It was suggested [14,[25][26][27]88] that a real understanding of the major stabilizing factors may only come from analysis of the components of the net energies related to each particular physical factors and type of interaction (i.e. with solvent or intermolecular).…”

“…Partial solution of this problem may be accomplished within the framework of energy analysis, whose objective is to determine the 'energy profile' of the binding reaction, i.e. to find out what physical factors (van der Waals, electrostatic, hydrophobic etc) and to what extent contribute to experimentally measured thermodynamic potentials [6,[12][13][14][15]. Even more important outcome would be the determination of correlation of particular energy terms, related to particular physical factors, and some biological parameter (e.g.…”