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The identification of novel, high affinity AQP9 inhibitors in an intracellular binding site

Wacker, Soeren J.; Aponte-Santamaria, Camilo; Kjellbom, Per LU ; Nielsen, Soren; de Groot, Bert L. and Rûtzler, Michael LU (2013) In Molecular Membrane Biology 30(3). p.246-260
Abstract
Background: The involvement of aquaporin (AQP) water and small solute channels in the etiology of several diseases, including cancer, neuromyelitis optica and body fluid imbalance disorders, has been suggested previously. Furthermore, results obtained in a mouse model suggested that AQP9 function contributes to hyperglycemia in type-2 diabetes. In addition, the physiological role of several AQP family members remains poorly understood. Small molecule inhibitors of AQPs are therefore desirable to further study AQP physiological and pathophysiological functions. Methods: The binding of recently established AQP9 inhibitors to a homology model of AQP9 was investigated by molecular dynamics simulations and molecular docking. Putative inhibitor... (More)
Background: The involvement of aquaporin (AQP) water and small solute channels in the etiology of several diseases, including cancer, neuromyelitis optica and body fluid imbalance disorders, has been suggested previously. Furthermore, results obtained in a mouse model suggested that AQP9 function contributes to hyperglycemia in type-2 diabetes. In addition, the physiological role of several AQP family members remains poorly understood. Small molecule inhibitors of AQPs are therefore desirable to further study AQP physiological and pathophysiological functions. Methods: The binding of recently established AQP9 inhibitors to a homology model of AQP9 was investigated by molecular dynamics simulations and molecular docking. Putative inhibitor binding sites identified with this procedure were modified by site-directed mutagenesis. Active compounds were measured in a mammalian cell water permeability assay of mutated AQP9 isoforms and tested for changes in inhibitory effects. Controls: Three independent cell lines were established for each mutated AQP9 isoform and functionality of mutant isoforms was established. Principal findings: We have identified putative binding sites of recently established AQP9 inhibitors. This information facilitated successful identification of novel AQP9 inhibitors with low micromolar IC50 values in a cell based assay by in silico screening of a compound library targeting specifically this binding site. Significance: We have established a successful strategy for AQP small molecule inhibitor identification. AQP inhibitors may be relevant as experimental tools, to enhance our understanding of AQP function, and in the treatment of various diseases. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Aquaporin, small molecule inhibitor, molecular docking
in
Molecular Membrane Biology
volume
30
issue
3
pages
246 - 260
publisher
Informa Healthcare
external identifiers
  • wos:000318033700002
  • scopus:84876739868
ISSN
0968-7688
DOI
10.3109/09687688.2013.773095
language
English
LU publication?
yes
id
a6a2f842-7b58-44c8-9af7-a7e9e40fb23a (old id 3853669)
date added to LUP
2013-06-20 07:56:59
date last changed
2019-06-09 03:53:38
@article{a6a2f842-7b58-44c8-9af7-a7e9e40fb23a,
  abstract     = {Background: The involvement of aquaporin (AQP) water and small solute channels in the etiology of several diseases, including cancer, neuromyelitis optica and body fluid imbalance disorders, has been suggested previously. Furthermore, results obtained in a mouse model suggested that AQP9 function contributes to hyperglycemia in type-2 diabetes. In addition, the physiological role of several AQP family members remains poorly understood. Small molecule inhibitors of AQPs are therefore desirable to further study AQP physiological and pathophysiological functions. Methods: The binding of recently established AQP9 inhibitors to a homology model of AQP9 was investigated by molecular dynamics simulations and molecular docking. Putative inhibitor binding sites identified with this procedure were modified by site-directed mutagenesis. Active compounds were measured in a mammalian cell water permeability assay of mutated AQP9 isoforms and tested for changes in inhibitory effects. Controls: Three independent cell lines were established for each mutated AQP9 isoform and functionality of mutant isoforms was established. Principal findings: We have identified putative binding sites of recently established AQP9 inhibitors. This information facilitated successful identification of novel AQP9 inhibitors with low micromolar IC50 values in a cell based assay by in silico screening of a compound library targeting specifically this binding site. Significance: We have established a successful strategy for AQP small molecule inhibitor identification. AQP inhibitors may be relevant as experimental tools, to enhance our understanding of AQP function, and in the treatment of various diseases.},
  author       = {Wacker, Soeren J. and Aponte-Santamaria, Camilo and Kjellbom, Per and Nielsen, Soren and de Groot, Bert L. and Rûtzler, Michael},
  issn         = {0968-7688},
  keyword      = {Aquaporin,small molecule inhibitor,molecular docking},
  language     = {eng},
  number       = {3},
  pages        = {246--260},
  publisher    = {Informa Healthcare},
  series       = {Molecular Membrane Biology},
  title        = {The identification of novel, high affinity AQP9 inhibitors in an intracellular binding site},
  url          = {http://dx.doi.org/10.3109/09687688.2013.773095},
  volume       = {30},
  year         = {2013},
}