Thiazide and other Cl-benzenesulfonamide-bearing clinical drug affinities for human carbonic anhydrases.

Twelve carbonic anhydrase (CA) isoforms catalyze carbon dioxide hydration to bicarbonate and acid protons and are responsible for many biological functions in human body. Despite their vital functions, they are also responsible for, or implicated in, numerous ailments and diseases such as glaucoma,...

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Autores principales:	Lina Baranauskiene, Lina Škiudaitė, Vilma Michailovienė, Vytautas Petrauskas, Daumantas Matulis
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/55d026cf7907438ea567f363bddbd6df
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spelling	oai:doaj.org-article:55d026cf7907438ea567f363bddbd6df2021-12-02T20:10:05ZThiazide and other Cl-benzenesulfonamide-bearing clinical drug affinities for human carbonic anhydrases.1932-620310.1371/journal.pone.0253608https://doaj.org/article/55d026cf7907438ea567f363bddbd6df2021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0253608https://doaj.org/toc/1932-6203Twelve carbonic anhydrase (CA) isoforms catalyze carbon dioxide hydration to bicarbonate and acid protons and are responsible for many biological functions in human body. Despite their vital functions, they are also responsible for, or implicated in, numerous ailments and diseases such as glaucoma, high altitude sickness, and cancer. Because CA isoforms are highly homologous, clinical drugs designed to inhibit enzymatic activity of a particular isoform, can also bind to others with similar affinity causing toxic side effects. In this study, the affinities of twelve CA isoforms have been determined for nineteen clinically used drugs used to treat hypertension related diseases, i.e. thiazides, indapamide, and metolazone. Their affinities were determined using a fluorescent thermal shift assay. Stopped flow assay and isothermal titration calorimetry were also employed on a subset of compounds and proteins to confirm inhibition of CA enzymatic activity and verify the quantitative agreement between different assays. The findings of this study showed that pharmaceuticals could bind to human CA isoforms with variable affinities and inhibit their catalytic activity, even though the drug was intended to interact with a different (non-CA) protein target. Relatively minor structural changes of the compounds may cause significant changes in affinity and selectivity for a particular CA isoform.Lina BaranauskieneLina ŠkiudaitėVilma MichailovienėVytautas PetrauskasDaumantas MatulisPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 6, p e0253608 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Lina Baranauskiene Lina Škiudaitė Vilma Michailovienė Vytautas Petrauskas Daumantas Matulis Thiazide and other Cl-benzenesulfonamide-bearing clinical drug affinities for human carbonic anhydrases.
description	Twelve carbonic anhydrase (CA) isoforms catalyze carbon dioxide hydration to bicarbonate and acid protons and are responsible for many biological functions in human body. Despite their vital functions, they are also responsible for, or implicated in, numerous ailments and diseases such as glaucoma, high altitude sickness, and cancer. Because CA isoforms are highly homologous, clinical drugs designed to inhibit enzymatic activity of a particular isoform, can also bind to others with similar affinity causing toxic side effects. In this study, the affinities of twelve CA isoforms have been determined for nineteen clinically used drugs used to treat hypertension related diseases, i.e. thiazides, indapamide, and metolazone. Their affinities were determined using a fluorescent thermal shift assay. Stopped flow assay and isothermal titration calorimetry were also employed on a subset of compounds and proteins to confirm inhibition of CA enzymatic activity and verify the quantitative agreement between different assays. The findings of this study showed that pharmaceuticals could bind to human CA isoforms with variable affinities and inhibit their catalytic activity, even though the drug was intended to interact with a different (non-CA) protein target. Relatively minor structural changes of the compounds may cause significant changes in affinity and selectivity for a particular CA isoform.
format	article
author	Lina Baranauskiene Lina Škiudaitė Vilma Michailovienė Vytautas Petrauskas Daumantas Matulis
author_facet	Lina Baranauskiene Lina Škiudaitė Vilma Michailovienė Vytautas Petrauskas Daumantas Matulis
author_sort	Lina Baranauskiene
title	Thiazide and other Cl-benzenesulfonamide-bearing clinical drug affinities for human carbonic anhydrases.
title_short	Thiazide and other Cl-benzenesulfonamide-bearing clinical drug affinities for human carbonic anhydrases.
title_full	Thiazide and other Cl-benzenesulfonamide-bearing clinical drug affinities for human carbonic anhydrases.
title_fullStr	Thiazide and other Cl-benzenesulfonamide-bearing clinical drug affinities for human carbonic anhydrases.
title_full_unstemmed	Thiazide and other Cl-benzenesulfonamide-bearing clinical drug affinities for human carbonic anhydrases.
title_sort	thiazide and other cl-benzenesulfonamide-bearing clinical drug affinities for human carbonic anhydrases.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/55d026cf7907438ea567f363bddbd6df
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Thiazide and other Cl-benzenesulfonamide-bearing clinical drug affinities for human carbonic anhydrases.

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