Thermodynamics of aryl-dihydroxyphenyl-thiadiazole binding to human Hsp90

• Published in: PloS one Vol. 7; no. 5; p. e36899
• Main Authors: Kazlauskas, Egidijus, Petrikaitė, Vilma, Michailovienė, Vilma, Revuckienė, Jurgita, Matulienė, Jurgita, Grinius, Leonas, Matulis, Daumantas
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 24-05-2012; Public Library of Science (PLoS)
• Subjects: Analysis; Aromatic compounds; Binding; Biochemistry; Biology; Biotechnology; Calorimetry; Chemistry; Design; Dissection; Enthalpy; Entropy; Enzymes; Free energy; Functional groups; Gibbs free energy; Heat shock proteins; HSP90 Heat-Shock Proteins - antagonists & inhibitors; HSP90 Heat-Shock Proteins - metabolism; Hsp90 protein; Humans; Inhibitors; Ligands; Protein Binding; Protonation; Specific heat; Thermal properties; Thermodynamics; Thiadiazoles; Thiadiazoles - chemistry; Thiadiazoles - pharmacology; Titration; Titration calorimetry; Lithuania
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0036899

The design of specific inhibitors against the Hsp90 chaperone and other enzyme relies on the detailed and correct understanding of both the thermodynamics of inhibitor binding and the structural features of the protein-inhibitor complex. Here we present a detailed thermodynamic study of binding of aryl-dihydroxyphenyl-thiadiazole inhibitor series to recombinant human Hsp90 alpha isozyme. The inhibitors are highly potent, with the intrinsic K(d) approximately equal to 1 nM as determined by isothermal titration calorimetry (ITC) and thermal shift assay (TSA). Dissection of protonation contributions yielded the intrinsic thermodynamic parameters of binding, such as enthalpy, entropy, Gibbs free energy, and the heat capacity. The differences in binding thermodynamic parameters between the series of inhibitors revealed contributions of the functional groups, thus providing insight into molecular reasons for improved or diminished binding efficiency. The inhibitor binding to Hsp90 alpha primarily depended on a large favorable enthalpic contribution combined with the smaller favorable entropic contribution, thus suggesting that their binding was both enthalpically and entropically optimized. The enthalpy-entropy compensation phenomenon was highly evident when comparing the inhibitor binding enthalpies and entropies. This study illustrates how detailed thermodynamic analysis helps to understand energetic reasons for the binding efficiency and develop more potent inhibitors that could be applied for therapeutic use as Hsp90 inhibitors.