title: Is TEA an inhibitor for human Aquaporin-1?
abstract: 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.
authors.affiliation: Department of Theoretical and Computational Biophysics, Max-Planck Institute for Biophysical Chemistry, Am Fassberg 11, Göttingen, Germany.
authors.forename: E Matthias
authors.initials: EM
authors.lastname: Müller
authors.forename: Jochen S
authors.initials: JS
authors.lastname: Hub
authors.forename: Helmut
authors.initials: H
authors.lastname: Grubmüller
authors.forename: Bert L
authors.initials: BL
authors.lastname: de Groot
mesh_terms: D000818:Animals; D051398:Aquaporin 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001665:Binding Sites / Q000187:drug effects; D003198:Computer Simulation; D005260:Female; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D009865:Oocytes / Q000378:metabolism; D010539:Permeability; D026902:Potassium Channel Blockers / Q000378:metabolism / Q000494:pharmacology*; D019789:Tetraethylammonium / Q000378:metabolism / Q000494:pharmacology*; D014982:Xenopus laevis
chemical_list: D026902:Potassium Channel Blockers; D051398:Aquaporin 1; D019789:Tetraethylammonium