Abstract

A drug molecule should bind to its target with high affinity and selectivity. Since the binding affinity is a combined function of the binding enthalpy and the binding entropy, extremely high affinity requires that both terms contribute favorably to binding. The binding enthalpy, however, is notoriously more difficult to optimize than the binding entropy, a fact that has resulted in thermodynamically-unbalanced molecules that do not achieve optimal potency. In fact, with current technologies, the enthalpic optimization of drug candidates may take years and only appear in second-generation products. Within that context, it is not surprising that structure/activity relationships (SAR) that explicitly incorporate the interplay between enthalpy and entropy and accelerate the optimization process are being developed and gaining popularity.

Definition of Terms
Enthalpy -- is a measure of the total energy of a thermodynamic system. It includes the internal energy, which is the energy required to create a system, and the amount of energy required to make room for it by displacing its environment and establishing its volume and pressure. Chemical properties:

Enthalpy of reaction, defined as the enthalpy change observed in a constituent of a thermodynamic system when one mole of substance reacts completely. Enthalpy of formation, defined as the enthalpy change observed in a constituent of a thermodynamic system when, one mole of a compound is formed from its elementary antecedents. Enthalpy of combustion, defined as the enthalpy change observed in a constituent of a thermodynamic system, when one mole of a substance combusts completely with oxygen. Enthalpy of hydrogenation, defined as the enthalpy change observed in a constituent of a thermodynamic system, when one mole of an unsaturated compound reacts completely with an excess of hydrogen to form a saturated compound. Enthalpy of atomization, defined as the enthalpy change required to atomize one mole of compound completely. Enthalpy of neutralization, defined as the enthalpy change observed in a constituent of a thermodynamic system, when one mole of water is produced when an acid and a base react. Standard Enthalpy of solution, defined as the enthalpy change observed in a constituent of a thermodynamic system, when one mole of an solute is dissolved completely in an excess of solvent. Standard enthalpy of Denaturation (biochemistry), defined as the enthalpy change required to denature one mole of compound. Enthalpy of hydration, defined as the enthalpy change observed when one mole of gaseous ions are completely dissolved in water forming one mole of aqueous ions.

Physical properties:

Enthalpy of fusion, defined as the enthalpy change required to completely change the state of one mole of substance between solid and liquid states. Enthalpy of vaporization, defined as the enthalpy change required to completely change the state of one mole of substance between liquid and gaseous states. Enthalpy of sublimation, defined as the enthalpy change required to completely change the state of one mole of substance between solid and gaseous states.

Lattice enthalpy, defined as the energy required to separate one mole of an ionic compound into separated gaseous ions to an infinite distance apart (meaning no force of attraction).

Entropy is a thermodynamic property that can be used to determine the energy not available forwork in a thermodynamic process, such as in energy conversion devices, engines, or machines.

Thermodynamic and statistical mechanics concepts

Entropy unit a non-S.I. unit of thermodynamic entropy, usually denoted "e.u." and equal to one calorie per Kelvin per mole, or 4.184Joules per Kelvin per mole.[54] Gibbs entropy the usual statistical mechanical entropy of a thermodynamic system. Boltzmann entropy a type of Gibbs entropy, which neglects internal statistical correlations in the overall particle distribution. Tsallis entropy a generalization of the standard Boltzmann-Gibbs entropy. Standard molar entropy is the entropy content of one mole of substance, under conditions of standard temperature and pressure. Residual entropy the entropy present after a substance is cooled arbitrarily close to absolute zero. Entropy of mixing the change in the entropy when two different chemical substances or components are mixed. Loop entropy is the entropy lost upon bringing together two residues of a polymer within a prescribed distance. Conformational entropy is the entropy associated with the physical arrangement of a polymer chain that assumes a compact orglobular state in solution. Entropic force a microscopic force or reaction tendency related to system organization changes, molecular frictional considerations, and statistical variations. Free entropy an entropic thermodynamic potential analogous to the free energy. Entropic explosion an explosion in which the reactants undergo a large change in volume without releasing a large amount of heat. Entropy change a change in entropy dS between two equilibrium states is given by the heat transferred dQrev divided by the absolute temperature T of the system in this interval.[55] Sackur-Tetrode entropy the entropy of a monatomic classical ideal gas determined via quantum considerations.

Review of Related Literature

Two different classes of forces determine the binding of a drug molecule to its target: attractive forces like van der Waals and hydrogen bonding interactions between drug and protein and repulsive forces, like the hydrophobic effect that tends to force the drug out of the aqueous solvent into a hydrophobic cavity. Since these forces contribute differently to the enthalpy and entropy changes, the thermodynamic signature, i.e. the proportion by which the enthalpy and entropy contribute to binding [9,10] provides a unique experimental way of characterizing the binding mode of a drug molecule. The enthalpy change associated with the interaction between drug and protein is difficult to optimize because it is composed of two major conflicting contributions1: the favorable enthalpy associated with the formation of hydrogen bonds and van der Waals contacts and the unfavorable enthalpy associated with the desolvation of polar groups. Van der Waals interactions are maximized by a perfect geometric fit between drug and target, while the strength of hydrogen bonds is maximal when the distance and angle between acceptors and donors are optimal. If the distance and angle are sub-optimal, the enthalpic contribution of a hydrogen bond does not simply become smaller and eventually approach zero, it actually becomes unfavorable. The reason behind this observation is that hydrogen bond donor and acceptor groups in the compound are hydrogen-bonded to water prior to binding. In binding energetics the real question is, how strong is the hydrogen bond that any given group forms with the protein, relative to the hydrogen bond that the same group forms with water prior to binding? The strength of the bonds with water are reflected in the enthalpy of desolvating those groups. The enthalpy penalty associated with the desolvation of polar groups commonly used in drug design is in the order of 8 kcal/mol at 25C (1 cal = 4.18 joules), which is about one order of magnitude higher than that of non-polar groups (see review and compilation of experimental values in [12]). Therefore, a favorable interaction enthalpy is an indication that the drug establishes good interactions with the target and that those interactions are strong enough to compensate the unfavorable enthalpy associated with desolvation. Conversely, an unfavorable binding enthalpy usually indicates that polar groups are not forming strong bonds with the target and that the desolvation penalty dominates. Structure-based drug design is not yet capable of engineering hydrogen bonds down to the tenths of one angstrom that are required to achieve a favorable enthalpy contribution. On the other hand, structure/activity relationships (SAR) extended to three dimensions by the incorporation of enthalpy and entropy data in addition to binding affinity, are capable of identifying optimal locations for hydrogen bond donors and acceptors.

``Conclusion
Binding is a process controlled by thermodynamics. For many years, the underlying thermodynamic variables (H, S) have not been utilized as guiding tools in drug development, due in part to a lack of adequate microcalorimetric instrumentation and appropriate formalisms for data interpretation and analysis. This situation is rapidly changing as better instruments with the required sensitivity, throughput and data processing capabilities have become available. It is evident that the enthalpic optimization of a compound is critical for achieving extremely high affinity. In addition, because the enthalpy and entropy changes reflect different types of interactions, other drug properties, like selectivity, are also affected by the enthalpy/entropy balance (thermodynamic signature) of a compound. Enthalpic optimization is difficult but can be facilitated by monitoring the enthalpic and entropic consequences of introducing or modifying different chemical functionalities. Traditionally, optimization has been driven by affinity; however, a multidimensional approach that also tracks the enthalpic and entropic contributions to affinity can yield faster and better results.