Thermodynamics of Ligand Binding and Efficiency

Abstract

b S Supporting Information T he primary goal of any drug discovery effort is to increase the potency of prospective compounds to the greatest degree possible while also optimizing the many other physical properties necessary for drug development. In most cases, little effort is invested in understanding the underlying thermodynamic quantities of enthalpy and entropy that are responsible for determining free energy. More recently, it has become common to recast binding free energies in terms of ligand efficiency, that is, the potency per heavy atom.1À5 Ligand efficiency and the thermodynamic properties (ΔH and ΔS) can provide insights into ligand binding that go beyond simple comparisons of potency. It has been suggested that more efficient ligands and ligands with more negative enthalpies of binding 6À8 provide better starting points for lead optimization. While these two concepts have generally been considered independently, an argument will be provided here that they are related.With regard to enthalpy and entropy of binding, Friere and others 6,9 have presented an intriguing argument that drugs (ligands) that bind predominantly due to favorable enthalpies enjoy certain advantages over drugs where binding is driven predominantly by entropy. Some of the arguments in favor of enthalpy are that enthalpic interactions improve selectivity due to their geometric specificity, and they are inherently more efficient since they tend to be larger in magnitude than entropic effects. The second point already hints to an effect on overall ligand efficiency. The case for ligand efficiency has been made extensively in the literature and is now well accepted. Recent work 4,8,10,11 has shown that the standard definition of ligand efficiency is problematic for comparing ligands of disparate size because ligand efficiency is itself a function of molecular size. One question that arises in this connection is the degree to which enthalpy and entropy contribute to the observed decrease in average efficiencies as ligands become larger. Entropy is commonly regarded as a problem for larger ligands since presumably more conformational degrees of freedom should be lost upon binding. Indeed, this was the logic employed by Andrews 2 for including a correction factor in his group additivity scheme based on the number of rotatable bonds. In a previous paper, computational analysis of the contribution of conformational entropy showed no discernible trend 4 with respect to ligand size. The experimental measurement of the thermodynamics of ligand binding can be routinely accomplished through techniques such as isothermal titration calorimetry (ITC).12 However, because of the complexity, quantity of protein required, and lowthroughput of ITC experiments, the enthalpy and entropy of ligand binding are not routinely measured. Through the work of a number of primarily academic laboratories, there has been a steady growth in the availability of this data for a variety of protein targets. Some of this data has been archived in the publicly available ...

The role of ligand efficiency metrics in drug discovery

“…Analysis of experimental ITC data 33,41 across a wide range of chemotypes shows that the average entropy efficiency is little changed with size (supplementary Figure S1), but narrows in moving from small to large ligands. 42 By contrast, the enthalpy efficiencies show a much more dramatic trend with increasing size, which is similar to the trend seen with the overall LE values (ie derived from G). Very favorable enthalpy efficiencies are common for small ligands, but the average, and most favorable, enthalpy efficiencies for larger ligands are systematically reduced (see supplementary Figure S1).…”

“…This was demonstrated with simple model systems 39 and is further supported by subsequent analysis of enthalpy and entropy efficiencies 42 showing that the size dependency is related to enthalpy (see Supplementary Figure S1). …”

“…Hence the overall trend in G related LE is mainly a consequence of enthalpy (H) efficiency. 40,42 These results suggest that the effects of conformational entropy may not be as significant as is commonly believed. In contrast to size, both lipophilic enthalpy and lipophilic entropy efficiencies tend to decrease with increasing lipophilicity (see Supplementary Figure S1).…”

Entropy–enthalpy transduction caused by conformational shifts can obscure the forces driving protein–ligand binding

“…Moreover, information on changes in entropy and enthalpy can usefully guide the design of improved drug molecules (1), with advantageous specificity (2) and physical properties (3). However, calorimetric studies of biomolecular binding and folding often reveal unexpected changes in entropy and enthalpy that are difficult to interpret in terms of physical driving forces (4)(5)(6)(7)(8). Some of these puzzling results are instances of entropy-enthalpy compensation (9), a common but not universal (10,11) phenomenon in which perturbations of a system that increase the enthalpy also increase the entropy or vice versa; therefore, the net change in the free energy remains small.…”

The Role of Molecular Simulations in the Development of Inhibitors of Amyloid β-Peptide Aggregation for the Treatment of Alzheimer’s Disease

“…82 The authors found a good correlation between experimental binding affinities and the calculated binding free energies, leading them to speculate that the predicted binding sites were a good model to explain the experimental findings, though it is known that enthalpic factors alone do not necessarily produce accurate binding energies in docking studies. 86 In the final example of docking small molecules to Aβ fibrils, Keshet et al docked a small library of structurally distinct molecules to 20 different Aβ 40 fibril models. The authors concluded that Congo Red (a dye molecule), myricetin (a flavonoid), and melatonin (a neurotransmitter) shared common binding sites on the fibril.…”