36
M. P. Evstigneev and A. V. Shestopalova
in understanding the mechanism of binding, as well as provides quantitative information on thermodynamics of binding in terms of Gibbs free energy (ΔG), enthalpy
(ΔH), entropy (ΔS) and heat capacity (ΔC p ) changes. In general it is considered that
such approach provides a scientific basis for rational drug design, but what might be
the link to designing of new drugs? In very first approximation the thermodynamical parameters of binding may be correlated with biological activity of the drug
(for reviews see [93, 94]). The typical examples are the semisynthetic antibiotic
Novantrone (an anthracycline derivative), which is widely used in the treatment
of leukemia [95], and bis-doxorubicin (a doxorubicin derivative), which exhibits
activity against multidrug-resistant tumour cells [96]. It follows that a manipulation
by the parameters of drug-NA binding by means of directed chemical synthesis of
the drug molecules may potentially lead to creation of new drugs. The problem
behind this is that experimentally-measured ΔG, ΔН and ΔS are made up of the sum
of contributions from various types of physical interactions (see Ref. [97] and references therein), viz. van der Waals, electrostatic, hydrophobic etc:
(2.1)
where ΔG i (or ΔH i , ΔS i ) stands for the contribution of the i-th physical factor to ΔG
(or ΔH, ΔS).
Any modification in the structure of a ligand in general case will likely lead to
unpredictable change in magnitudes of the energy components in Eq. (2.1) and the
effect of their summation in Eq. (2.1) may change the magnitudes of ΔG/ΔH/ΔS or
even leave them unchanged. It follows that direct comparison of experimentallymeasured thermodynamic parameters for different ligands is unlikely to be very
meaningful and may even lead to erroneous conclusions. A common manifestation
of that problem is encountered in the enthalpy-entropy compensation for binding
processes in aqueous media [98, 99]. Additionally, the long-existing discussion exists in the literature on what forces (van der Waals, electrostatic or hydrophobic) or
types of interactions (solute-solvent or solute-solute) dominate the stacking interactions in solution [100, 101], which makes a thermodynamic analysis intrinsically
ambiguous. Nevertheless, greater understanding of the thermodynamics of drugNA binding processes can be achieved if the problem of energy partitioning (also
known as energy parsing or energy decomposition) is solved [97, 102]. This needs
an independent calculation of the energy components in Eq. (2.1) and comparison
of the results to the experimentally-measured total Gibbs free energy. Knowledge
of these contributions is crucial in managing the properties of ligand binding with
NA by manipulating the distribution of energy over various physical factors governing the reaction of complexation. However, there is a fundamental problem behind
any attempt to parse experimentally-measured thermodynamic quantities ΔG, ΔН,
ΔS, viz. it is generally not possible to measure independently the contribution of
specific energy term to the total binding energies. Nevertheless, as we shall demonstrate below, partial overcome of this problem may be achieved using the methods
of computational chemistry.
∆
∆ ∆
∆
∆ ∆
G
H S
G
H S
i
i
i
i
(
, )
(
,
)
or
o r
= ∑
M. P. Evstigneev and A. V. Shestopalova
in understanding the mechanism of binding, as well as provides quantitative information on thermodynamics of binding in terms of Gibbs free energy (ΔG), enthalpy
(ΔH), entropy (ΔS) and heat capacity (ΔC p ) changes. In general it is considered that
such approach provides a scientific basis for rational drug design, but what might be
the link to designing of new drugs? In very first approximation the thermodynamical parameters of binding may be correlated with biological activity of the drug
(for reviews see [93, 94]). The typical examples are the semisynthetic antibiotic
Novantrone (an anthracycline derivative), which is widely used in the treatment
of leukemia [95], and bis-doxorubicin (a doxorubicin derivative), which exhibits
activity against multidrug-resistant tumour cells [96]. It follows that a manipulation
by the parameters of drug-NA binding by means of directed chemical synthesis of
the drug molecules may potentially lead to creation of new drugs. The problem
behind this is that experimentally-measured ΔG, ΔН and ΔS are made up of the sum
of contributions from various types of physical interactions (see Ref. [97] and references therein), viz. van der Waals, electrostatic, hydrophobic etc:
(2.1)
where ΔG i (or ΔH i , ΔS i ) stands for the contribution of the i-th physical factor to ΔG
(or ΔH, ΔS).
Any modification in the structure of a ligand in general case will likely lead to
unpredictable change in magnitudes of the energy components in Eq. (2.1) and the
effect of their summation in Eq. (2.1) may change the magnitudes of ΔG/ΔH/ΔS or
even leave them unchanged. It follows that direct comparison of experimentallymeasured thermodynamic parameters for different ligands is unlikely to be very
meaningful and may even lead to erroneous conclusions. A common manifestation
of that problem is encountered in the enthalpy-entropy compensation for binding
processes in aqueous media [98, 99]. Additionally, the long-existing discussion exists in the literature on what forces (van der Waals, electrostatic or hydrophobic) or
types of interactions (solute-solvent or solute-solute) dominate the stacking interactions in solution [100, 101], which makes a thermodynamic analysis intrinsically
ambiguous. Nevertheless, greater understanding of the thermodynamics of drugNA binding processes can be achieved if the problem of energy partitioning (also
known as energy parsing or energy decomposition) is solved [97, 102]. This needs
an independent calculation of the energy components in Eq. (2.1) and comparison
of the results to the experimentally-measured total Gibbs free energy. Knowledge
of these contributions is crucial in managing the properties of ligand binding with
NA by manipulating the distribution of energy over various physical factors governing the reaction of complexation. However, there is a fundamental problem behind
any attempt to parse experimentally-measured thermodynamic quantities ΔG, ΔН,
ΔS, viz. it is generally not possible to measure independently the contribution of
specific energy term to the total binding energies. Nevertheless, as we shall demonstrate below, partial overcome of this problem may be achieved using the methods
of computational chemistry.
∆
∆ ∆
∆
∆ ∆
G
H S
G
H S
i
i
i
i
(
, )
(
,
)
or
o r
= ∑