Ligand Preorganization May Be Accompanied by Entropic Penalties in Protein–Ligand Interactions

Benfield, Aaron P.; Teresk, Martin G.; Plake, Hilary R.; DeLorbe, John E.; Millspaugh, Laura E.; Martin, Stephen F.

doi:10.1002/anie.200600844

Cited by 70 publications

(75 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…As an interesting contrast to our globally constrained macrocycle, this report involved a locally constrained cyclopropane-based peptidomimetic that targeted the Grb2 SH2 domain. 46 Unlike our prior study, this system employed a more closely matching scission control ligand, and included structural characterization that revealed the binding modes of both constrained and control ligands. A weakness of the calorimetric technique is if the observed parameters dip below the threshold where significant numerical analysis can occur.…”

Section: Evaluating the Thermodynamic Behavior Of Conformational Consmentioning

confidence: 98%

“…[33][34][35][36][37] Since then, a handful of studies have appeared in which constrained systems have been examined in a controlled fashion, and which have taken advantage of the availability of calorimetric methods to measure the underlying thermodynamic binding parameters; these have included carbohydrates 38,39 as well as peptides [40][41][42][43] and peptidomimetic scaffolds. [44][45][46] FIGURE 1 Theoretical behavior of conformational entropy in the case of a flexible ligand and corresponding constrained analog.…”

Section: Conformational Constraint In Protein Ligand Design and The Imentioning

confidence: 99%

See 1 more Smart Citation

Conformational constraint in protein ligand design and the inconsistency of binding entropy

Udugamasooriya

Spaller

2008

Biopolymers

View full text Add to dashboard Cite

It is an accepted practice in ligand design to introduce conformational constraint with the expectation of improving affinity, justified by the theoretical possibility that an unfavorable change in binding entropy will be reduced. This rationale of minimizing the entropic penalty through imposing structural constraints upon a ligand, however, has been voiced more often than verified. Here we examine three modified cyclic peptides, along with multiple versions of their linear control analogs, and determine their thermodynamic parameters when binding the same host, the third PDZ domain (PDZ3) of the mammalian postsynaptic density-95 (PSD-95) protein. To begin a two-stage investigation, the initial evaluation involved solution binding studies with isothermal titration calorimetry (ITC), which provided the changes in Gibbs free energy (DeltaG), enthalpy (DeltaH), and entropy (TDeltaS) upon formation of the protein-ligand complex. In the second stage, a selected macrocycle along with two matched linear controls were subjected to more rigorous analysis by ITC, which included (1) change in heat of buffer ionization (DeltaH(ion)) titrations, to examine the role of proton transfer events; (2) change in heat capacity (DeltaC(p)) determinations, to indirectly probe the nature of the binding surface; and (3) osmotic stress experiments, to evaluate desolvation effects and quantitate water release. Together, these demonstrate that the entropic relationship between a macrocyclic ligand and a linear counterpart can be a complex one that is difficult to rationalize. Further, the addition of constraint can, counterintuitively, lead to a less favorable change in binding entropy. This underscores the need to use matched linear control ligands to assure that comparisons are made in a meaningful manner.

show abstract

Section: Evaluating the Thermodynamic Behavior Of Conformational Consmentioning

confidence: 98%

Section: Conformational Constraint In Protein Ligand Design and The Imentioning

confidence: 99%

Conformational constraint in protein ligand design and the inconsistency of binding entropy

Udugamasooriya

Spaller

2008

Biopolymers

View full text Add to dashboard Cite

show abstract

“…1 Because of their large size and inherent flexibility, biomacromolecules are particularly notorious in this regard and they can exhibit counter-intuitive behaviours, such as entropic stabilization of the complex due to increased flexibility upon binding. 2,3 Accounting for the flexibility of proteins is, in fact, one of the major difficulties in structure-based drug design, and significant methodological improvements will be necessary to deal with it appropriately. structure-activity relationships (SAR), because conformational effects can substantially modify the binding affinity of related compounds (see ref.…”

Section: Introductionmentioning

confidence: 99%

Toward accurate relative energy predictions of the bioactive conformation of drugs

2008

View full text Add to dashboard Cite

Quantifying the relative energy of a ligand in its target-bound state (i.e. the bioactive conformation) is essential to understand the process of molecular recognition, to optimize the potency of bioactive molecules and to increase the accuracy of structure-based drug design methods. This is, nevertheless, seriously hampered by two interrelated issues, namely the difficulty in carrying out an exhaustive sampling of the conformational space and the shortcomings of the energy functions, usually based on parametric methods of limited accuracy. Matters are further complicated by the experimental uncertainty on the atomic coordinates, which precludes a univocal definition of the bioactive conformation. In this article we investigate the relative energy of bioactive conformations introducing two major improvements over previous studies: the use sophisticated QM-based methods to take into account both the internal energy of the ligand and the solvation effect, and the application of physically meaningful constraints to refine the bioactive conformation. On a set of 99 drug-like molecules, we find that, contrary to previous observations, two thirds of bioactive conformations lie within 0.5 kcal mol(-1) of a local minimum, with penalties above 2.0 kcal mol(-1) being generally attributable to structural determination inaccuracies. The methodology herein described opens the door to obtain quantitative estimates of the energy of bioactive conformations and can be used both as an aid in refining crystallographic structures and as a tool in drug discovery.

show abstract

“…In a similar series of studies, ∆G, ∆H, and ∆S for forming complexes of 14 and 15 with the Grb2 SH2 domain were determined by ITC [14]. All compounds exhibited low micromolar affinities.…”

Section: Thermodynamic and Structural Studies Of Grb2 Sh2 Binding Ligmentioning

confidence: 99%

Preorganization in biological systems: Are conformational constraints worth the energy?

Martin

2007

Pure and Applied Chemistry

Self Cite

View full text Add to dashboard Cite

It is generally assumed that preorganizing a flexible ligand in the three-dimensional shape it adopts when bound to a macromolecular receptor will provide a derivative having an increased binding affinity, primarily because the rigidified molecule is expected to benefit from a lesser entropic penalty during complexation. We now provide the first experimental evidence that demonstrates this common belief is not universally true. Indeed, we find that ligand preorganization may be accompanied by an unfavorable entropy of binding, even when the constrained ligand exhibits a higher binding affinity than its flexible control. Thus, the effects that ligand preorganization have upon energetics and structure in protein-ligand interactions must be reevaluated.

show abstract

Ligand Preorganization May Be Accompanied by Entropic Penalties in Protein–Ligand Interactions

Abstract: A prevailing hypothesis in the field of molecular recognition in chemistry and biology is that the preorganization of flexible hosts and their guests in a manner corresponding to the three-

Cited by 70 publications

References 32 publications

Conformational constraint in protein ligand design and the inconsistency of binding entropy

Conformational constraint in protein ligand design and the inconsistency of binding entropy

Toward accurate relative energy predictions of the bioactive conformation of drugs

Preorganization in biological systems: Are conformational constraints worth the energy?

Contact Info

Product

Resources

About