Discovery of Novel Human Aquaporin-1 Blockers

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.A quaporins (AQPs) are passive membrane channels that, in many species, facilitate highly efficient yet strictly selective permeation of water and small solutes across lipid bilayers. AQPs can be divided into two major subclasses, the aquaporin subfamiliy that selectively transports water and the aquaglyceroporin family that in addition transports small uncharged molecules such as glycerol.

Challenging AQP4 druggability for NMO-IgG antibody binding using molecular dynamics and molecular interaction fields

“…The present paper reports how the harmonized use of advanced biophysical and drug discovery strategies, already proved to be valuable for other aquaporins [57], allow in approaching very challenging targets as AQP4. Supported by very recent experimental observations [25,56], we suggest that the surface of loop A and, more importantly, of the residues flanking its basis forms a druggable cavity and, thus, a valuable target for the structure-based design of compounds able to inhibit NMO-IgG binding to AQP4 in NMO patients.…”

Bumetanide Derivatives AqB007 and AqB011 Selectively Block the Aquaporin-1 Ion Channel Conductance and Slow Cancer Cell Migration

“…Other arylsulfonamides have been proposed as blockers of AQP4 channels (Huber et al, 2009). A distinct class of agents acting on the external side of the membrane to block human AQP1 water flux has been identified as a source of candidate lead compounds for drug development (Seeliger et al, 2013).…”

Experimental Evaluation of Proposed Small-Molecule Inhibitors of Water Channel Aquaporin-1

“…Compounds 1, 2, and 3 were identified by virtual (computational) screening of ∼10 6 compounds of the ZINC database and testing 14 compounds for inhibition of osmotic swelling in AQP1-expressing Xenopus laevis oocytes (Seeliger et al, 2013). The compounds were identified by molecular docking computations to a part of the extracellular surface of human AQP1.…”

“…More recently, a variety of approaches, including high-throughput screening and computational chemistry, have yielded compounds with reported AQP1 inhibition or activation activity (Migliati et al, 2009;Mola et al, 2009;Seeliger et al, 2013;Yool et al, 2013;To et al, 2015;Patil et al, 2016), as summarized in Fig. 1 [tributyl-(2,4,5-trichlorophenoxy) …”