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Is TEA an inhibitor for human Aquaporin-1?

Excessive water uptake through aquaporins can be life threatening, and disregulation of water permeability causes many diseases. Therefore, reversible aquaporin inhibitors are highly desired. In this paper, we identified the binding site for tetraethylammonium (TEA) of the membrane water channel aqu...

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Detalles Bibliográficos
Autores principales: Müller, E. Matthias, Hub, Jochen S., Grubmüller, Helmut, de Groot, Bert L.
Formato: Texto
Lenguaje:English
Publicado: Springer-Verlag 2008
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2756347/
https://www.ncbi.nlm.nih.gov/pubmed/18196268
http://dx.doi.org/10.1007/s00424-007-0422-0
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author Müller, E. Matthias
Hub, Jochen S.
Grubmüller, Helmut
de Groot, Bert L.
author_facet Müller, E. Matthias
Hub, Jochen S.
Grubmüller, Helmut
de Groot, Bert L.
author_sort Müller, E. Matthias
collection PubMed
description Excessive water uptake through aquaporins can be life threatening, and disregulation of water permeability causes many diseases. Therefore, reversible aquaporin inhibitors are highly desired. In this paper, we identified the binding site for tetraethylammonium (TEA) of the membrane water channel aquaporin-1 by a combined molecular docking and molecular dynamics simulation approach. The binding site identified from docking studies was independently confirmed with an unbiased molecular dynamics simulation of an aquaporin tetramer embedded in a lipid membrane, surrounded by a 100-mM tetraethylammonium solution in water. A third independent assessment of the binding site was obtained by umbrella sampling simulations. These simulations, in addition, revealed a binding affinity of more than 17 kJ/mol, corresponding to an IC(50) value of << 3 mM. Finally, we observed in our simulations a 50% reduction of the water flux in the presence of TEA, in agreement with water permeability measurements on aquaporin expressed in oocytes. These results confirm TEA as a putative lead for an aquaporin-1 inhibitor.
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spelling pubmed-27563472009-10-07 Is TEA an inhibitor for human Aquaporin-1? Müller, E. Matthias Hub, Jochen S. Grubmüller, Helmut de Groot, Bert L. Pflugers Arch Transporters Excessive water uptake through aquaporins can be life threatening, and disregulation of water permeability causes many diseases. Therefore, reversible aquaporin inhibitors are highly desired. In this paper, we identified the binding site for tetraethylammonium (TEA) of the membrane water channel aquaporin-1 by a combined molecular docking and molecular dynamics simulation approach. The binding site identified from docking studies was independently confirmed with an unbiased molecular dynamics simulation of an aquaporin tetramer embedded in a lipid membrane, surrounded by a 100-mM tetraethylammonium solution in water. A third independent assessment of the binding site was obtained by umbrella sampling simulations. These simulations, in addition, revealed a binding affinity of more than 17 kJ/mol, corresponding to an IC(50) value of << 3 mM. Finally, we observed in our simulations a 50% reduction of the water flux in the presence of TEA, in agreement with water permeability measurements on aquaporin expressed in oocytes. These results confirm TEA as a putative lead for an aquaporin-1 inhibitor. Springer-Verlag 2008-01-15 2008-07 /pmc/articles/PMC2756347/ /pubmed/18196268 http://dx.doi.org/10.1007/s00424-007-0422-0 Text en © Springer-Verlag 2007
spellingShingle Transporters
Müller, E. Matthias
Hub, Jochen S.
Grubmüller, Helmut
de Groot, Bert L.
Is TEA an inhibitor for human Aquaporin-1?
title Is TEA an inhibitor for human Aquaporin-1?
title_full Is TEA an inhibitor for human Aquaporin-1?
title_fullStr Is TEA an inhibitor for human Aquaporin-1?
title_full_unstemmed Is TEA an inhibitor for human Aquaporin-1?
title_short Is TEA an inhibitor for human Aquaporin-1?
title_sort is tea an inhibitor for human aquaporin-1?
topic Transporters
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2756347/
https://www.ncbi.nlm.nih.gov/pubmed/18196268
http://dx.doi.org/10.1007/s00424-007-0422-0
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