Compensating Enthalpic and Entropic Changes Hinder Binding Affinity Optimization

Abstract

A common strategy to improve the potency of drug candidates is to introduce chemical functionalities, like hydrogen bond donors or acceptors, at positions where they are able to establish strong interactions with the target. However, it is often observed that the added functionalities do not necessarily improve potency even if they form strong hydrogen bonds. Here, we explore the thermodynamic and structural basis for those observations. KNI-10033 is a potent experimental HIV-1 protease inhibitor with picomolar affinity against the wild-type enzyme (K(d) = 13 pm). The potency of the inhibitor is the result of favorable enthalpic (DeltaH = -8.2 kcal/mol) and entropic (-TDeltaS = -6.7 kcal/mol) interactions. The replacement of the thioether group in KNI-10033 by a sulfonyl group (KNI-10075) results in a strong hydrogen bond with the amide of Asp 30B of the HIV-1 protease. This additional hydrogen bond improves the binding enthalpy by 3.9 kcal/mol; however, the enthalpy gain is completely compensated by an entropy loss, resulting in no affinity change. Crystallographic and thermodynamic analysis of the inhibitor/protease complexes indicates that the entropy losses are due to a combination of conformational and solvation effects. These results provide a set of practical guidelines aimed at overcoming enthalpy/entropy compensation and improve binding potency.

Rationalising sequence selection by ligand assemblies in the DNA minor groove: the case for thiazotropsin A

“…29 Recent studies of HIV-1 protease inhibitors have found that a slight modification to the structure of a ligand can lead to completely different thermodynamic profiles. 36 The previous suggestion that minor groove-binding could be mainly entropically driven was based on a limited number of examples and was qualified by the need to critically test the hypothesis by expanding the database of thermodynamic data for minor groove binders. The studies detailed here for thiazotropsin A provide important new insights into this process and indeed extend the thermodynamic database, considerably adding to the significance of our findings in this work.…”

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

“…However, introducing H-bond donors or acceptors to establish stronger protein-ligand interactions often results in the absence of net gain in binding affinity [19,28]. Rather than targeting protein-ligand interactions per se, H-bonds are also reported to promote ligand binding affinity by displacing protein-bound water molecules into the bulk solvent [29,30,31,32].…”

Binding free energy, energy and entropy calculations using simple model systems

“…However, retrospective analyses [1] have shown that a rational modification often only leads to a moderate improvement in DG bind , due to a compensation of the enthalpy (DH) and the entropy (DS). A shift from mainly entropically driven binding towards mainly enthalpically driven binding, or vice versa, is commonly observed [2][3][4]. This phenomenon is largely due to the current trend to optimise ligands for more enthalpic binding.…”

“…Equation (4) implies that DS may be obtained from a linear regression over multiple DA estimates at different temperatures, obtained using, for example, TI. The third approach estimates DS directly from TI [8], using Eq.…”