Thermodynamics of aryl-dihydroxyphenyl-thiadiazole binding to human Hsp90.

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 a...

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Autores principales:	Egidijus Kazlauskas, Vilma Petrikaitė, Vilma Michailovienė, Jurgita Revuckienė, Jurgita Matulienė, Leonas Grinius, Daumantas Matulis
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/fdc06ac0a3514bc5b45020c5b1c4c9db
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spelling	oai:doaj.org-article:fdc06ac0a3514bc5b45020c5b1c4c9db2021-11-18T07:17:35ZThermodynamics of aryl-dihydroxyphenyl-thiadiazole binding to human Hsp90.1932-620310.1371/journal.pone.0036899https://doaj.org/article/fdc06ac0a3514bc5b45020c5b1c4c9db2012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22655030/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203The 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.Egidijus KazlauskasVilma PetrikaitėVilma MichailovienėJurgita RevuckienėJurgita MatulienėLeonas GriniusDaumantas MatulisPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 5, p e36899 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Egidijus Kazlauskas Vilma Petrikaitė Vilma Michailovienė Jurgita Revuckienė Jurgita Matulienė Leonas Grinius Daumantas Matulis Thermodynamics of aryl-dihydroxyphenyl-thiadiazole binding to human Hsp90.
description	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.
format	article
author	Egidijus Kazlauskas Vilma Petrikaitė Vilma Michailovienė Jurgita Revuckienė Jurgita Matulienė Leonas Grinius Daumantas Matulis
author_facet	Egidijus Kazlauskas Vilma Petrikaitė Vilma Michailovienė Jurgita Revuckienė Jurgita Matulienė Leonas Grinius Daumantas Matulis
author_sort	Egidijus Kazlauskas
title	Thermodynamics of aryl-dihydroxyphenyl-thiadiazole binding to human Hsp90.
title_short	Thermodynamics of aryl-dihydroxyphenyl-thiadiazole binding to human Hsp90.
title_full	Thermodynamics of aryl-dihydroxyphenyl-thiadiazole binding to human Hsp90.
title_fullStr	Thermodynamics of aryl-dihydroxyphenyl-thiadiazole binding to human Hsp90.
title_full_unstemmed	Thermodynamics of aryl-dihydroxyphenyl-thiadiazole binding to human Hsp90.
title_sort	thermodynamics of aryl-dihydroxyphenyl-thiadiazole binding to human hsp90.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/fdc06ac0a3514bc5b45020c5b1c4c9db
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Thermodynamics of aryl-dihydroxyphenyl-thiadiazole binding to human Hsp90.

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