How Much Binding Affinity Can be Gained by Filling a Cavity?

Abstract

Binding affinity optimization is critical during drug development. Here we evaluate the thermodynamic consequences of filling a binding cavity with functionalities of increasing van der Waals radii (-H, -F, -Cl and CH3) that improve the geometric fit without participating in hydrogen bonding or other specific interactions. We observe a binding affinity increase of two orders of magnitude. There appears to be three phases in the process. The first phase is associated with the formation of stable van der Waals interactions. This phase is characterized by a gain in binding enthalpy and a loss in binding entropy, attributed to a loss of conformational degrees of freedom. For the specific case presented in this paper, the enthalpy gain amounts to −1.5 kcal/mol while the entropic losses amount to +0.9 kcal/mol resulting in a net 3.5-fold affinity gain. The second phase is characterized by simultaneous enthalpic and entropic gains. This phase improves the binding affinity 25-fold. The third phase represents the collapse of the trend and is triggered by the introduction of chemical functionalities larger than the binding cavity itself (CH(CH3)2). It is characterized by large enthalpy and affinity losses. The thermodynamic signatures associated with each phase provide guidelines for lead optimization.

Enthalpy screen of drug candidates

“…In this figure, the enthalpy values determined with the enthalpy screen have been plotted against previously published values [9, 10, 19–23] determined in this laboratory by standard ITC titrations under identical conditions. The enthalpy values cover a wide range, from highly exothermic (−11 kcal/mol) to endothermic compounds (2.7 kcal/mol).…”

“… * Published values are from (a) [10]; (b) [23]; (c) [20]; (d) [19]; (e) [9]; (f) [21]; (g) [30]; (h) [29]. …”

“…A favorable binding enthalpy is associated with the presence of strong hydrogen bonds and van der Waals interactions between ligand and protein [9, 10]. On the contrary, an unfavorable binding enthalpy usually reflects the unproductive desolvation of polar groups; i.e.…”

It Is Important to Compute Intramolecular Hydrogen Bonding in Drug Design?

“…From an analysis of ligands containing multiple hydrogen bond donor groups it is apparent that within a single ligand it is very difficult to accommodate more than about two or three hydrogen bond donor groups with the precise geometry needed for the maximum enthalpic energy benefit arising from the optimal three dimensional positioning of a hydrogen bond [199]. This phenomenon is often discussed in the context of entropy-enthalpy compensation [200]. As a result, as the number of potential hydrogen bond donors in a ligand increases it becomes increasingly likely that they will not contribute in a positive sense to ligand binding and likely will detract from ligand binding.…”

Thermodynamic Evaluation of the Binding of Bisphosphonates to Human Farnesyl Pyrophosphate Synthase

“…Better van der Waals interactions can be achieved by improving the shape of the drug molecule to better fit the binding cavity. 41) A well-placed hydrogen bond can make a favorable enthalpic contribution on the order of −4 to −5 kcal/mol, a property that will be directly reflected in the binding affinity if enthalpy/entropy compensation is not present. 42) Thus, an in-depth understanding of drug/target interactions can be achieved when the binding thermodynamics are considered in connection with structure-based information.…”