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  Discovery of novel human aquaporin-1 blockers.

Seeliger, D., Zapater, C., Krenc, D., Haddoub, R., Flitsch, S., Beitz, E., et al. (2013). Discovery of novel human aquaporin-1 blockers. ACS Chemical Biology, 8(1), 249-256. doi:10.1021/cb300153z.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-000E-CAE7-0 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0027-C869-D
Genre: Journal Article

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http://pubs.acs.org/doi/pdf/10.1021/cb300153z (Publisher version)
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 Creators:
Seeliger, D.1, Author              
Zapater, Cinta, Author
Krenc, Dawid, Author
Haddoub, Rose, Author
Flitsch, Sabine, Author
Beitz, Eric, Author
Cerdà, Joan, Author
De Groot, B. L.1, Author              
Affiliations:
1Research Group of Computational Biomolecular Dynamics, MPI for biophysical chemistry, Max Planck Society, ou_578573              

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 Abstract: Human aquaporin-1 (hAQP1) is a water channel found in many tissues and potentially involved in several human pathologies. Selective inhibitors of hAQP1 are discussed as novel treatment opportunities for glaucoma, brain edema, inflammatory pain, and certain types of cancer. However, only very few potent and chemically attractive blockers have been reported to date. In this study we present three novel hAQP1 blockers that have been identified by virtual screening and inhibit water flux through hAQP1 in Xenopus laevis oocyte swelling assays at low micromolar concentrations. The newly discovered compounds display no chemical similarity to hitherto known hAQP1 blockers and bind at the extracellular entrance of the channel, close to the ar/R selectivity filter. Futhermore, mutagenesis studies showed that Lys36, which is not conserved among the hAQP family, is crucially involved in binding and renders the discovered compounds suitable as leads for the development of selective hAQP1 inhibitors.

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Language(s): eng - English
 Dates: 2012-10-312013-01-18
 Publication Status: Published in print
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 Rev. Method: Peer
 Identifiers: DOI: 10.1021/cb300153z
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Title: ACS Chemical Biology
Source Genre: Journal
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Pages: - Volume / Issue: 8 (1) Sequence Number: - Start / End Page: 249 - 256 Identifier: -