Beyond Affinity: Enthalpy–Entropy Factorization Unravels Complexity of a Flat Structure–Activity Relationship for Inhibition of a tRNA-Modifying Enzyme

Abstract

Lead optimization focuses on binding-affinity improvement. If a flat structure-activity relationship is detected, usually optimization strategies are abolished as unattractive. Nonetheless, as affinity is composed of an enthalpic and entropic contribution, factorization of both can unravel the complexity of a flat, on first sight tedious SAR. In such cases, the binding free energy of different ligands can be rather similar, but it can factorize into enthalpy and entropy distinctly. We investigated the thermodynamic signature of two classes of lin-benzopurines binding to tRNA-guanine transglycosylase. While the differences are hardly visible in the free energy, they involve striking enthalpic and entropic changes. Analyzing thermodynamics along with structural features revealed that one ligand set binds to the protein without inducing significant changes compared to the apo structure; however, the second series provokes complex adaptation, leading to a conformation similar to the substrate-bound state. In the latter state, a cross-talk between two pockets is suggested.

The Use of Thermodynamic and Kinetic Data in Drug Discovery: Decisive Insight or Increasing the Puzzlement?

“…ITC measurements can record, when studied under different buffer conditions, whether a change in protonation state occurs, and this can drive a tailored design of pK a properties of ligands in order to optimize their binding in parallel with appropriate bioavailability. [30] An ITC experiment observes the total binding event all the way from individually solvated protein and ligand to the formed complex with changed degrees of freedom and it includes all participating water molecules. This will not be disclosed solely by considering affinity data.…”

“…Finally, ITC data can help to understand flat structureactivity relationships and distinguish ligand binding to alternative conformations of a target protein, an effect that cannot be unraveled solely by considering affinity data. [30] An ITC experiment observes the total binding event all the way from individually solvated protein and ligand to the formed complex with changed degrees of freedom and it includes all participating water molecules. It thus reflects-apart from binding-a more complete picture, including many additional phenomena that give rise to superimposed compensatory effects also resulting from concurrent changes of the protein and solvent environment.…”

Application of ITC-Based Characterization of Thermodynamic and Kinetic Association of Ligands With Proteins in Drug Design

“…The application of thermodynamic data in combination with complex structures in hit-to-lead optimization has been reported in several cases ( Abel et al, 2008 ; Neeb et al, 2014 ; Cramer et al, 2017b ). We also successfully utilized this strategy in the process of lead discovery of phosphodiesterase type 5 (PDE5) and fatty-acid binding protein 4 (FABP4), and found that the water molecule or water network in the ligand binding pocket plays an important role in association of compounds with targeting proteins.…”

Aryl Bis‐Sulfonamide Inhibitors of IspF from Arabidopsis thaliana and Plasmodium falciparum

“…[c] Values werecalculated with ACD/Percepta [43] at pH 8.0. www.chemmedchem.org off equation on the inhibitory data from the photometric assay. [26,27]…”

“…Synthesis and biological activity of designed monosulfonamide ligands 5-(Chlorosulfonyl)isophthalic acid (27)w as converted into compound 28,then monobrominated to provide buildingb lock 29 (Scheme 4). Precursor 30 was prepared followingapublished protocol, [38] reduced to alcohol 31,a nd brominated to afford building block 32.…”