49
The correlation coefficients of the terms in Eq. (2.5) with ΔG exp do not exceed
0.5 and do not allow selecting the terms which exert the maximal impact on the
binding affinity. It means that the principal physical factors, such as VDW, EL,
HYD, HB, give approximately equal contribution to the variability of ΔG exp with
the type of ligand.
2.4.6 Summary of the Results, and Implications on the Use
of Energy Analysis in Rational Drug Design
Energy analysis of ligand-NA interactions, sketched out above for typical DNA intercalators, DNA minor groove binders and RNA binders, enables us to answer the
key question, viz. “What physical factors stabilize/destabilize the ligand-NA complexes in solution and what are their relative importance?” The follow-up question
now is “How one can use the results of the energy analysis, say, in rational design
of new drugs?”
The set of stabilizing and destabilizing energies aligned in descending order, as
the main outcome of the energy analysis, provides a fundamental knowledge on
energetics of binding reactions in solution but, in fact, gives little idea on the way
how one can manipulate the magnitude of ΔG exp and, eventually, the medico-biological effect of the NA-binding drugs [123, 129]. It is considered that the search of
the factor which is most strongly correlated with the equilibrium binding constant
K
G
RT
=
−
exp
exp
∆
may give this idea. If it is known what factor modulates the
ligand affinity to DNA (VDW, hydrophobic, electrostatics or else), it becomes more
clear what type of atomic group must be chemically added/substituted in the ligand
structure in order to amplify the contribution of this particular physical factor to
the net energy of binding, resulting in increase of ΔG exp . In particular, it was shown
above that in the case of DNA intercalators the “managing” of the binding affinity
may be achieved via the VDW factor, whereas for the group of DNA minor groove
binders the EL energy appears to be the key factor. However, such approach may
be of value if the binding affinity is the target property to be manipulated, or if no
sufficient data on biological activity of the studied group of ligands is available, and
the amplification of the binding affinity to bioreceptor remains the only possible
strategy. The case if relevant biological data are available, search of correlations
between the biological activity and specific energy terms may have real practical
outcome. Let us consider such possibility taking as an example the results of analysis performed for the group of MGB binders in Ref. [129 ].
Table 2.7 contains the calculated values of the energy terms for the set of MGBligands and the ID 50 factor for the same ligands (which is a micromolar concentration of the drug, needed for 50 % suppression of L1210 leukemia cell growth).
It must be noted that rather limited dataset presented in Table 2.7 does not allow reporting on statistically reliable correlation, nevertheless, the qualitative level
of correlation may be considered. It is seen that the highest correlation of the ID 50
2 Structure, Thermodynamics and Energetics of Drug-DNA Interactions
The correlation coefficients of the terms in Eq. (2.5) with ΔG exp do not exceed
0.5 and do not allow selecting the terms which exert the maximal impact on the
binding affinity. It means that the principal physical factors, such as VDW, EL,
HYD, HB, give approximately equal contribution to the variability of ΔG exp with
the type of ligand.
2.4.6 Summary of the Results, and Implications on the Use
of Energy Analysis in Rational Drug Design
Energy analysis of ligand-NA interactions, sketched out above for typical DNA intercalators, DNA minor groove binders and RNA binders, enables us to answer the
key question, viz. “What physical factors stabilize/destabilize the ligand-NA complexes in solution and what are their relative importance?” The follow-up question
now is “How one can use the results of the energy analysis, say, in rational design
of new drugs?”
The set of stabilizing and destabilizing energies aligned in descending order, as
the main outcome of the energy analysis, provides a fundamental knowledge on
energetics of binding reactions in solution but, in fact, gives little idea on the way
how one can manipulate the magnitude of ΔG exp and, eventually, the medico-biological effect of the NA-binding drugs [123, 129]. It is considered that the search of
the factor which is most strongly correlated with the equilibrium binding constant
K
G
RT
=
−
exp
exp
∆
may give this idea. If it is known what factor modulates the
ligand affinity to DNA (VDW, hydrophobic, electrostatics or else), it becomes more
clear what type of atomic group must be chemically added/substituted in the ligand
structure in order to amplify the contribution of this particular physical factor to
the net energy of binding, resulting in increase of ΔG exp . In particular, it was shown
above that in the case of DNA intercalators the “managing” of the binding affinity
may be achieved via the VDW factor, whereas for the group of DNA minor groove
binders the EL energy appears to be the key factor. However, such approach may
be of value if the binding affinity is the target property to be manipulated, or if no
sufficient data on biological activity of the studied group of ligands is available, and
the amplification of the binding affinity to bioreceptor remains the only possible
strategy. The case if relevant biological data are available, search of correlations
between the biological activity and specific energy terms may have real practical
outcome. Let us consider such possibility taking as an example the results of analysis performed for the group of MGB binders in Ref. [129 ].
Table 2.7 contains the calculated values of the energy terms for the set of MGBligands and the ID 50 factor for the same ligands (which is a micromolar concentration of the drug, needed for 50 % suppression of L1210 leukemia cell growth).
It must be noted that rather limited dataset presented in Table 2.7 does not allow reporting on statistically reliable correlation, nevertheless, the qualitative level
of correlation may be considered. It is seen that the highest correlation of the ID 50
2 Structure, Thermodynamics and Energetics of Drug-DNA Interactions